2025/09/02 更新

写真a

タケノウチ トシキ
武内 俊樹
Toshiki Takenouchi
所属
医歯薬学域 教授
職名
教授
プロフィール

【研究業績の掲載について】「論文」は英語論文のみ、「MISC」「書籍等出版物」は日本語論文等としています。また、「講演・口頭発表等」は依頼講演のみ掲載しています。

学位

  • 博士(医学) ( 慶應義塾大学 )

研究キーワード

  • 小児科学

  • 神経学

  • 遺伝医学

  • 新生児学

研究分野

  • ライフサイエンス / 胎児医学、小児成育学

  • ライフサイエンス / ゲノム生物学

学歴

  • 慶應義塾大学   School of Medicine  

    1996年 - 2002年

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    国名: 日本国

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経歴

  • 岡山大学   学術研究院 医歯薬学域 小児発達病因病態学分野   教授

    2024年 - 現在

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  • 慶應義塾大学   医学部小児科学   専任講師

    2017年 - 2024年

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    国名:日本国

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  • 内閣官房   健康・医療戦略室   参事官補佐

    2013年 - 2014年

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    国名:日本国

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  • NewYork-Presbyterian Hospital, Weill Cornell Medical Center   Department of Pediatrics   Resident and Clinical Fellow

    2006年 - 2010年

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    国名:アメリカ合衆国

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  • Boston Children's Hospital   Department of Medicine   Resident

    2004年 - 2005年

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    国名:アメリカ合衆国

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  • 慶應義塾大学病院   研修医

    2002年 - 2004年

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    国名:日本国

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  • 慶應義塾大学   医学部小児科学   准教授

    2024年

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  • Brooklyn Hospital Center   Department of Pediatrics   Resident

    2005年 - 2006年

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    国名:アメリカ合衆国

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所属学協会

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委員歴

  • 日本医療研究開発機構 (AMED)   難治性疾患実用化研究事業 評価委員  

    2024年 - 現在   

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  • 日本小児遺伝学会   倫理および指針委員会 委員長  

    2024年 - 現在   

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  • 日本小児遺伝学会   理事  

    2024年 - 現在   

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  • 日本レックリングハウゼン病学会   第16回学術大会長  

    2024年 - 2025年   

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  • 日本レックリングハウゼン病学会   理事  

    2023年 - 現在   

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  • 日本てんかん学会   評議員  

    2021年 - 現在   

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    団体区分:学協会

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  • 日本医療機能評価機構   産科医療補償制度 審査委員会 委員  

    2020年 - 現在   

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  • 日本先天異常学会   評議員  

    2020年 - 現在   

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    団体区分:学協会

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  • 日本人類遺伝学会   評議員  

    2019年 - 現在   

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    団体区分:学協会

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  • 日本小児神経学会   評議員  

    2016年 - 現在   

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    団体区分:学協会

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  • 慶應義塾大学病院   保険委員会委員長・医療保険指導部部長  

    2022年 - 2024年   

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  • 東京都社会保険診療報酬請求書審査委員会   審査員  

    2020年 - 2024年   

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論文

  • Parkinsonism in Spinocerebellar Ataxia with Axonal Neuropathy Caused by Adult-onset COA7 Variants: A Case Report. 査読 国際誌

    Shogo Ouchi, Kazuhiro Ishii, Kenjiro Kosaki, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Akira Tamaoka

    BMC Neurology   23 ( 1 )   211 - 211   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Individuals with variants of cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial functional-related gene, exhibit symptoms of spinocerebellar ataxia with axonal neuropathy before the age of 20. However, COA7 variants with parkinsonism or adult-onset type cases have not been described. CASE PRESENTATION: We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58. Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A > G, NP_075565.2: p.Asp6Gly). Dopamine transporter single-photon emission computed tomography using a 123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum. However, 123I-metaiodobenzylguanidine myocardial scintigraphy showed normal sympathetic nerve function. Levodopa administration improved parkinsonism in this patient. CONCLUSIONS: COA7 gene variants may have caused parkinsonism in this case because mitochondrial function-related genes, such as parkin and PINK1, are known causative genes in some familial Parkinson's diseases.

    DOI: 10.1186/s12883-023-03202-w

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  • Ketogenic Diet in Action: Metabolic Profiling of Pyruvate Dehydrogenase Deficiency. 査読 国際誌

    Eri Ogawa, Takako Hishiki, Noriyo Hayakawa, Hisato Suzuki, Kenjiro Kosaki, Makoto Suematsu, Toshiki Takenouchi

    Molecular Genetics and Metabolism Reports   35   100968 - 100968   2023年6月

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    担当区分:最終著者   記述言語:英語  

    The pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.

    DOI: 10.1016/j.ymgmr.2023.100968

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  • Involvement of mTOR Pathway in Neurodegeneration in NSF-related Developmental and Epileptic Encephalopathy. 査読 国際誌

    Takahiro Hayashi, Naoko Yano, Kengo Kora, Atsushi Yokoyama, Kanako Maizuru, Taisei Kayaki, Kinuko Nishikawa, Mitsujiro Osawa, Akira Niwa, Toshiki Takenouchi, Atsushi Hijikata, Tsuyoshi Shirai, Hisato Suzuki, Kenjiro Kosaki, Megumu K Saito, Junko Takita, Takeshi Yoshida

    Human Molecular Genetics   32 ( 10 )   1683 - 1697   2023年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mammalian/mechanistic target of rapamycin (mTOR) pathway. Treatment with rapamycin, an mTOR inhibitor or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach.

    DOI: 10.1093/hmg/ddad008

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  • Oral Baclofen Therapy for Multifocal Spinal Myoclonus with TBC1D24 Variant. 査読 国際誌

    Yuka Murofushi, Itaru Hayakawa, Michiko Kawai, Yuichi Abe, Rika Kosaki, Hisato Suzuki, Toshiki Takenouchi, Masaya Kubota

    Movement Disorders Clinical Practice   10 ( 4 )   719 - 721   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/mdc3.13701

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  • A Novel Variant of ARPC4-related Neurodevelopmental Disorder. 査読 国際誌

    Yukiko Kuroda, Tatsuro Kumaki, Yoko Saito, Yumi Enomoto, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Kenji Kurosawa

    American Journal of Medical Genetics. Part a   191 ( 3 )   893 - 895   2023年3月

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    DOI: 10.1002/ajmg.a.63082

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  • Occult Cartilaginous Choristoma in a Child with Myelin Oligodendrocyte Glycoprotein Antibody-associated Encephalomyelitis. 国際誌

    Sayaka Enomoto, Hiroki Tsuchiya, Yoshiyuki Ayada, Yoshiki Takai, Toshiki Takenouchi

    Journal of Neuroimmunology   406   578674 - 578674   2025年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myelin oligodendrocyte glycoprotein antibody-associated disease is a central inflammatory demyelinating disorder that cause diverse neurological symptoms. Paraneoplastic neurologic syndromes occur in association with malignant neoplasms and manifest with a wide range of neuropsychiatric symptoms. Paraneoplastic neurological syndrome is rare in myelin oligodendrocyte glycoprotein antibody-associated disease and, when reported, is typically seen in adults. Herein, we report a 3-year-old girl who presented with lower limb paralysis, urinary retention, and seropositivity for myelin oligodendrocyte glycoprotein antibody. Her symptoms did not respond to various immunotherapies. She was incidentally found to have a cartilaginous choristoma in the neck, after surgical resection of which, she showed symptomatic recovery without recurrence. Immunohistochemical analysis of the resected tumor revealed expression of myelin oligodendrocyte glycoprotein within the cartilage tissue. Based on this case experience, children presenting with myelin oligodendrocyte glycoprotein antibody-associated disease who fail to respond to immunotherapies may need prompt screening for occult tumors.

    DOI: 10.1016/j.jneuroim.2025.578674

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  • Prenatal Brain Abnormalities in Sodium-Dependent Multivitamin Transporter Deficiency. 国際誌

    Eri Ogawa, Kenjiro Kosaki, Toshiki Takenouchi

    American Journal of Medical Genetics. Part a   197 ( 9 )   e64102   2025年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In treatable neurometabolic disorders, early diagnosis and prompt initiation of treatment are key to improved survival and outcomes. Biallelic variants in SLC5A6 cause sodium-dependent multivitamin transporter deficiency (OMIM # 618973), which is treatable with high-dose pantothenic acid, biotin, and alpha lipoic acid. So far, the onset has been postnatal in all reported patients. A review of the prenatal imaging showed ventriculomegaly at 32 weeks of gestation. After birth, the infant exhibited developmental regression. At 6 months of age, he developed acute metabolic shock in the setting of a urinary tract infection. Rapid exome analysis identified compound heterozygous pathogenic variants in SLC5A6 and confirmed the diagnosis of sodium-dependent multivitamin transporter deficiency. After the infant was initiated on treatment with high-dose biotin and pantothenic acid, we noted dramatic improvements in the hematological, cutaneous, cardiac, and gastrointestinal symptoms. Although the infant showed no further regression, he continued to have significant psychomotor disability. A review of the findings during pregnancy showed that the infant already had enlarged ventricles in late pregnancy, and neuroimaging on day 12 of birth showed signs of energy failure in late pregnancy. Our review of previously reported patients suggested no clear genotype-phenotype correlations, but there was little intrafamilial variability in disease onset. The present observation, for the first time, provides clinical evidence of a fetal onset in sodium-dependent multivitamin transporter deficiency. The high risk of recurrence and the low intrafamilial variability in disease onset suggest that identification and prenatal treatment in the high-risk group may be of significance.

    DOI: 10.1002/ajmg.a.64102

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  • 'Knowing and Treating Kosaki/Penttinen Syndrome' International Collaborative Consortium: Recommendations for Follow-up, Natural History and a Real-life Observational Study About Safety and Efficacy Profile of Tyrosine Kinase Inhibitors. 国際誌

    Yordi-Michaël Bouhatous, Cecilie Bredrup, Agnes Maurer, Liubinka Mirakovska, Alison Foster, Kenjiro Kosaki, Céline Jost, Jean-Baptiste Demoulin, Maxime Luu, Pierre Vabres, Jean-Emmanuel Kurtz, Elise Schaefer, Anne Guimier, Valerie Cormier-Daire, Derek Lim, Sarah Thompson, Lorin Olson, Hae Ryong Kwon, Cristina Aguirre-Rodriguez, Unai Hernandez-Dorronsoro, Itziar Martinez-Soroa, Helena Iznardo, José-Manuel Mascaró Jr, Eulalia Baselga, Silvia Kalantari, Alessandro Mussa, Andrea Gazzin, Diana Carli, Ingrid Svinvik, Hatice Mutlu-Albayrak, Sarah Bluefeather, Yuri Zarate, Toshiki Takenouchi, Thirona Naicker, Antoinette Chateau, Ashmika Gokhul, Anele Dube-Pule, Muzhirah Haniffa, Winnie Ong Peitee, Ann Nordgren, Maud Carpentier, Christine Binquet, Anne-Sophie Briffaut, Laurence Bal, Dinel Pond, Cecilie F Rustad, Marc Bardou, Laurence Faivre

    Journal of Medical Genetics   2025年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: 5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in PDGFRB. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes. MATERIAL AND METHODS: The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place. RESULTS: As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use. CONCLUSION: The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.

    DOI: 10.1136/jmg-2024-110600

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  • Novel SKIC3 Variants in Tricho-hepato-enteric Syndrome with Hemochromatosis. 国際誌

    Kayo Ochiai, Yoshinori Aoki, Naoshi Yamada, Murasaki Aman, Atsushi Yamashita, Masatoshi Yamaguchi, Daisuke Nakato, Toshiki Takenouchi, Kenjiro Kosaki, Yuki Kodama, Hiroshi Moritake

    Human Genome Variation   12 ( 1 )   14 - 14   2025年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tricho-hepato-enteric syndrome (THES), a rare autosomal recessive disorder caused by variants in the SKIC3 or SKIC2 gene, is characterized by intractable diarrhea, woolly hair, growth restriction and liver disease. Here we report a neonatal case of THES with neonatal hemochromatosis, in which the novel compound heterozygous SKIC3 variants NM_014639.4:c.815_816del p.(Gly272AlafsTer9) and NM_014639.4:c.2284G>A p.(Gly762Arg) were identified. Further research is needed to elucidate the mechanisms underlying iron metabolism dysregulation in THES.

    DOI: 10.1038/s41439-025-00318-y

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  • Immediate Therapeutic Response to Vigabatrin in Lissencephaly-Related Epileptic Spasms due to TUBA1A R402H Variant. 国際誌

    Toru Nagata, Takashi Shibata, Hiroki Tsuchiya, Mari Akiyama, Mitsuhiro Kato, Tomoyuki Akiyama, Toshiki Takenouchi

    American Journal of Medical Genetics. Part a   197 ( 7 )   e64030   2025年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.64030

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  • RHOA-associated Disorder Can Be Non-mosaic. 国際誌

    Daisuke Nakato, Naoya Morisada, Sota Iwatani, Chikako Nishida, Daisuke Watanabe, Mamiko Yamada, Hisato Suzuki, Fuyuki Miya, Kenjiro Kosaki, Toshiki Takenouchi

    European Journal of Medical Genetics   75   105019 - 105019   2025年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for RHOA variants. Conversely, no patients with non-mosaic germline variants of RHOA have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all RHOA variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2-3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic de novo germline variant RHOA:c.202C>A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of RHOA negates the previous notion that patients with RHOA variants are not viable. The differential diagnosis of a "non-mosaic" RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.

    DOI: 10.1016/j.ejmg.2025.105019

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  • De Novo CDKN1C Variant in Beckwith-wiedermann Spectrum with Atypical Complications. 国際誌

    Yuri Moriura, Yosuke Nishio, Shintaro Ichimura, Haruka Noda, Yoshihiro Tanahashi, Hikaru Yamamoto, Yuka Nakazawa, Taichi Oso, Yoshiaki Sato, Toshiki Takenouchi, Shinji Saitoh, Yukako Muramatsu, Tomoo Ogi

    Human Genome Variation   12 ( 1 )   9 - 9   2025年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Beckwith-Wiedemann spectrum (BWSp) is a genomic imprinting disorder characterized by a wide range of clinical features. Here we report an infant with BWSp and atypical features, for whom long-read sequencing confirmed a de novo CDKN1C variant that occurred on the maternally inherited allele and excluded other genetic etiologies. These findings not only expand the BWSp concept but also highlight the potential value of allelic origin analysis in cases with atypical presentations.

    DOI: 10.1038/s41439-025-00316-0

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  • A Girl with a De Novo PPP2R5D W207R Pathogenic Variant Was also Born with an Occipital Encephalocele. 国際誌

    Eijun Seki, Takeshi Uehara, Mamiko Yamada, Toshiki Takenouchi, Noriko Aida, Kenjiro Kosaki, Kenji Kurosawa

    Clinical Dysmorphology   34 ( 2 )   55 - 57   2025年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1097/MCD.0000000000000514

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  • PURA-related Neurodevelopmental Disorders: A Systematic Review on Genotype-phenotype Correlations. 国際誌

    Noritaka Taniguchi, Keisuke Watanuki, Daisuke Nakato, Toshiki Takenouchi, Kenjiro Kosaki, Hiroshi Koga

    Journal of Medical Genetics   62 ( 3 )   191 - 198   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Genotype-phenotype correlations in PURA-related neurodevelopmental disorders (PURA-NDDs) remain unclear. This systematic review aimed to clarify these correlations. METHODS: Searches of PubMed and Embase were conducted on 8 August 2024 to identify studies that had investigated genetically diagnosed PURA-NDDs (5q31.3 deletion syndrome and PURA syndrome). All types and languages of studies were included. Study quality was assessed using a 20-item criterion checklist. Genetic and clinical data were extracted from each article and genotype-phenotype correlations were explored. RESULTS: Our analysis included 46 studies encompassing 230 patients with PURA-NDDs (5q31.3 deletion syndrome 18 (8%) and PURA syndrome 212 (92%)). Patients with 5q31.3 deletion syndrome exhibited more congenital defects (50% vs 12%, p<0.0001), respiratory difficulties (94% vs 63%, p=0.013) and walking disability (94% vs 55%, p=0.0026) than patients with PURA syndrome. In PURA syndrome, protein-truncating (nonsense or frameshift) variants were associated with more speech deficits (93% vs 80%, p=0.014) than non-protein-truncating (missense or in-frame) variants. PURA variant location had no effect on congenital defect occurrence or neurodevelopmental outcome. Overall, respiratory difficulties, walking disability and speech deficits were more commonly observed in the following order: 5q31.3 deletion (94%, 94% and 100%, respectively), multiple PUR-repeat deletions (68%, 60% and 95%, respectively), single PUR-repeat deletion or alteration (61%, 53% and 85%, respectively), and deletion or alteration located outside PUR repeats (38%, 33% and 43%, respectively). CONCLUSION: The clinical severity of PURA-NDDs appears to be associated with the deletion/alteration size including PUR repeats rather than the location of PURA variants.

    DOI: 10.1136/jmg-2024-110379

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  • Brain Calcification in Congenital Heart Defects and Ectodermal Dysplasia (CHDED). 国際誌

    Daisuke Watanabe, Yohei Hasebe, Hideaki Yagasaki, Daisuke Nakato, Mamiko Yamada, Hisato Suzuki, Yosuke Kono, Yuto Sunaga, Masashi Yoshizawa, Hiromune Narusawa, Fuyuki Miya, Toshiki Takenouchi, Takeshi Inukai, Kenjiro Kosaki

    European Journal of Medical Genetics   73   104992 - 104992   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described. Calcifications were present in three patients with CHDED. (two patients; renal calcifications, one patient; brain calcifications). The organ distribution of calcifications in CHDED has been unclear. We report here another patient with CHDED and brain calcifications. The patient was a 9-month-old Japanese girl. She presented with heart defects and ectodermal dysplasia. At 6 months of age, she had generalized seizures, and a CT scan revealed calcifications in the bilateral deep cerebral white matter. The seizures resolved with the administration of levetiracetam. The patient had a de novo, heterozygous pathogenic variant, c.1808G > A, p.(Arg603His), in the PRKD1 gene. Together with the previously reported patients mentioned above, we demonstrated the role of the PRKD1 variant in brain calcification. We propose that PRKD1 and two genes, ITGB2 and JAM2, which are known to be associated with brain calcification, act through a common signaling pathway abnormality. In support of our hypothesis, there are some experimental results that link PRKD1 and JAM2. PRKD1 functions with the integrin ITGB2 as a partner. JAM2, which is associated with brain calcification and is critical for maintaining of the tight junction of the endothelial cells, interacts with integrins including ITGB2. Therefore, PRKD1 could lead to the pathological phenotype of brain calcification.

    DOI: 10.1016/j.ejmg.2024.104992

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  • Autosomal Recessive Cutis Laxa Type 1C with a Compound Heterozygous Frame Shift and Nonsense LTBP4 Variants. 国際誌

    Keiko Shoburu, Toshiki Nakamura, Makoto Ishitate, Hiroshi Yoshihashi, Toshiki Takenouchi, Tatsuo Kono, Hiroshi Hataya

    Pediatrics international : official journal of the Japan Pediatric Society   67 ( 1 )   e15893   2025年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ped.15893

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  • De Novo Variants in UPF1 Associated with Intellectual Disabilities: Human Genetic and Functional Evidences Using Drosophila Model 国際誌

    Daisuke Nakato, Yuri Yasue, Kohei Matsubara, Hisato Suzuki, Rika Kosaki, Toshiki Takenouchi, Mamiko Yamada, Fuyuki Miya, Toshiyuki Takano-Shimizu, Kenjiro Kosaki

    European Journal of Medical Genetics   72   104983 - 104983   2024年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    Nonsense-mediated mRNA decay represents a biologic clearing system against aberrant mRNAs harboring nonsense and frameshift mutations and depends on three factors, UPF1, UPF2, and UPF3 (UPF3A, UPF3B). While germline pathogenic variants of UPF3B and UPF2 are known to be associated with neurodevelopmental disorders, germline variants in UPF1 have not been reported, until date, as being associated with any human disorders. Herein, we report two unrelated patients with de novo UPF1 variants. Patient 1 was a 5-year-old girl with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. Patient 2 was a 2-year-old female child with intellectual disabilities and similar features. Trio exome analysis revealed a de novo heterozygous variant in UPF1 in both the patients (Patient 1: NM_002911.4): c.949_951del, p.(Asp317del); Patient 2: c.1984G>A, p.(Asp662Asn)). We conducted experiments using Drosophila models to evaluate the functional relevance of these UPF1 variants. Enforced expression of the wild-type Upf1 allele under the control of the pan-neuronal nSyb-GAL4 driver caused mortality, mostly at the pupal stage, but still yielded adult flies. By contrast, expression of the Asp294del (Asp317del in humans) variant caused embryonic or early larval lethality and that of the Asp643Asn (Asp662Asn in humans) caused third instar larval lethality; neither produced pupa nor adult fly. Thus, the developmental defects caused by the variants, especially Asp294del, were more severe than those caused by the wild-type allele. These observations suggest that both variants are deleterious mutations. In conclusion, germline variants in UPF1 are associated with intellectual disabilities in humans.

    DOI: 10.1016/j.ejmg.2024.104983

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  • Café-au-lait Spots and Cleft Palate: Not a Chance Association. 国際誌

    Mamiko Yamada, Katsumi Tanito, Hisato Suzuki, Daisuke Nakato, Fuyuki Miya, Toshiki Takenouchi, Kenjiro Kosaki

    The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association   61 ( 11 )   1932 - 1936   2024年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The recognition of syndromic forms of cleft palate is important for condition-specific management. Here, we report a patient with cleft palate, congenital heart disease, intellectual disability, and café-au-lait spots who had a deletion of chromosome 15q14. The identification of the precise breakpoints using a Nanopore-based long-read sequencer showed that the deletion spanned MEIS2 and SPRED1 loci. Cleft palate and café-au-lait spots can be ascribed to MEIS2 and SPRED1, respectively. Patients with cleft palate and café-au-lait spots should be encouraged to undergo a detailed genomic evaluation, including screening for a 15q14 deletion, to enable appropriate anticipatory medico-surgical management and genetic counseling.

    DOI: 10.1177/10556656231188205

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  • ASXL1-related Bohring-optiz Syndrome Complicated by Persistent Neonatal Pulmonary Hypertension and Abnormal Alveoli Formation. 国際誌

    Makoto Arioka, Shinji Nakamura, Katsufumi Nishioka, Kota Inoue, Yasuhiro Nakao, Yumi Miyai, Hirosuke Morita, Kosuke Koyano, Toshiki Takenouchi, Saneyuki Yasuda, Yoichi Chiba, Takashi Iwase, Masaki Ueno, Takashi Kusaka

    European Journal of Medical Genetics   72   104978 - 104978   2024年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a de novo frameshift variant in ASXL1. Autopsy revealed that the lung was at the saccular stage, equivalent to 28-34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in ASXL1.

    DOI: 10.1016/j.ejmg.2024.104978

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  • Biallelic Structural Variants in Three Patients with ERCC8-related Cockayne Syndrome and a Potential Pitfall of Copy Number Variation Analysis. 国際誌

    Daisuke Watanabe, Nobuhiko Okamoto, Yuichi Kobayashi, Hisato Suzuki, Mitsuhiro Kato, Shinji Saitoh, Yonehiro Kanemura, Toshiki Takenouchi, Mamiko Yamada, Daisuke Nakato, Masayuki Sato, Tatsuhiko Tsunoda, Kenjiro Kosaki, Fuyuki Miya

    Scientific Reports   14 ( 1 )   19741 - 19741   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC8 or ERCC6. Most pathogenic variants in ERCC8 are single nucleotide substitutions. Structural variants (SVs) have been reported in patients with ERCC8-related CS. However, comprehensive molecular detection, including SVs of ERCC8, in CS patients remains problematic. Herein, we present three Japanese patients with ERCC8-related CS in whom causative SVs were identified using whole-exome-based copy number variation (CNV) detection tools. One patient showed compound heterozygosity for a 259-kb deletion and a deletion of exon 4 which has previously been reported as an Asia-specific variant. The other two patients were homozygous for the same exon 4 deletion. The exon 4 deletion was detected only by the ExomeDepth software. Intrigued by the discrepancy in the detection capability of various tools for the SVs, we evaluated the analytic performance of four whole-exome-based CNV detection tools using an exome data set from 337 healthy individuals. A total of 1,278,141 exons were predicted as being affected by the 4 CNV tools. Interestingly 95.1% of these affected exons were detected by one tool alone. Thus, we expect that the use of multiple tools may improve the detection rate of SVs from aligned exome data.

    DOI: 10.1038/s41598-024-70831-7

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  • Digital Clubbing Without Hypoxia for Lysinuric Protein Intolerance. 国際誌

    Daisuke Watanabe, Yuko Tsujioka, Daisuke Nakato, Mamiko Yamada, Hisato Suzuki, Takuma Ohnishi, Naotaka Tamai, Toshihide Kijima, Toshiki Takenouchi, Fuyuki Miya, Satoshi Narumi, Kenjiro Kosaki

    European Journal of Medical Genetics   71   104967 - 104967   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production.

    DOI: 10.1016/j.ejmg.2024.104967

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  • SALL4 Deletion and Kidney and Cardiac Defects Associated with VACTERL Association. 国際誌

    Daisuke Watanabe, Daisuke Nakato, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Fuyuki Miya, Kenjiro Kosaki

    Pediatric nephrology (Berlin, Germany)   39 ( 8 )   2347 - 2349   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Congenital anomalies of the kidney and urinary tract (CAKUT) can be a part of the VACTERL association, which represents the non-random combination of the following congenital anomalies: vertebral anomalies, anal anomalies, cardiac anomalies, tracheal-esophageal anomalies, kidney anomalies, and limb anomalies. VACTERL association is generally considered to be a non-genetic condition. Exceptions include a patient with a heterozygous nonsense SALL4 variant and anal stenosis, tetralogy of Fallot, sacro-vertebral fusion, and radial and thumb anomalies. SALL4 encodes a transcription factor that plays a critical role in kidney morphogenesis. Here, we report a patient with VACTERL association and a heterozygous 128-kb deletion spanning SALL4 who presented with renal hypoplasia, radial and atrio-septal defects, and patent ductus arteriosus. The present report of SALL4 deletion, in addition to a previously reported patient with VACTERL association phenotype and SALL4 nonsense mutation, further supports the notion that SALL4 haploinsufficiency can lead to VACTERL association.

    DOI: 10.1007/s00467-024-06306-8

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  • Biallelic Loss-of-function Variants in the Centriolar Protein CCP110 Leads to a Ciliopathy-like Phenotype. 国際誌

    Hisato Suzuki, Yukako Muramatsu, Fuyuki Miya, Hideyuki Asada, Mamiko Yamada, Gen Nishimura, Kenjiro Kosaki, Toshiki Takenouchi

    European Journal of Medical Genetics   70   104955 - 104955   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CCP110 (centriolar coiled coil protein 110, also known as CP110) is one of the essential proteins localized in the centrosome that plays critical roles in the regulation of the cell cycle and also in the initiation of ciliogenesis. So far, no human congenital disorders have been identified to be associated with pathogenic variants of CCP110. Mice with biallelic loss-of-function variants of Ccp110 (Ccp110-/-) are known to manifest multiple organ defects, including a small body size, polydactyly, omphalocele, congenital heart defects, cleft palate, short ribs, and a small thoracic cage, a pattern of abnormalities closely resembling that in "ciliopathies" in humans. Herein, we report a 7-month-old male infant who presented with growth failure and skeletal abnormalities, including a narrow thorax and severe brachydactyly. Trio exome analysis of the genomic DNA of the patient and his parents showed that the patient was a compound heterozygote for truncating variants of CCP110, including a frameshift variant NM_001323572.2:c.856_857del, p.(Val286Leufs*5) inherited from the father, and a nonsense variant NM_001323572.2:c.1129C>T, p.(Arg377*) inherited from the mother. The strikingly similar pattern of malformations between Ccp110-/- mice and the 7-month-old male infant reported herein carrying unequivocal truncating CCP110 variants strongly supports the contention that CCP110 is a novel disease-causative gene.

    DOI: 10.1016/j.ejmg.2024.104955

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  • Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy. 国際誌

    Megumi Nishino, Mai Tanaka, Kazuo Imagawa, Katsuyuki Yaita, Takashi Enokizono, Tatsuyuki Ohto, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Kenjiro Kosaki, Hidetoshi Takada

    American journal of medical genetics. Part A   194 ( 7 )   e63575   2024年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

    DOI: 10.1002/ajmg.a.63575

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  • Truncating variants of the sterol recognition region of SHH cause hypertelorism phenotype rather than hypotelorism-holoprosencephaly. 国際誌

    Mamiko Yamada, Seiji Mizuno, Mie Inaba, Tomoko Uehara, Hidehito Inagaki, Hisato Suzuki, Fuyuki Miya, Toshiki Takenouchi, Hiroki Kurahashi, Kenjiro Kosaki

    American journal of medical genetics. Part A   194 ( 8 )   e63614   2024年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia-mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss-of-function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13-year-old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25-year-old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism-holoprosencephaly phenotype associated with loss-of-function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.

    DOI: 10.1002/ajmg.a.63614

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  • Successful Skipping of Abnormal Pseudoexon by Antisense Oligonucleotides in Vitro for a Patient with Beta-propeller Protein-associated Neurodegeneration. 国際誌

    Mamiko Yamada, Kazuhiro Maeta, Hisato Suzuki, Ryo Kurosawa, Toshiki Takenouchi, Tomonari Awaya, Masahiko Ajiro, Atsuko Takeuchi, Hisahide Nishio, Masatoshi Hagiwara, Fuyuki Miya, Masafumi Matsuo, Kenjiro Kosaki

    Scientific Reports   14 ( 1 )   6506 - 6506   2024年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro. The patient had developmental delay and later showed extrapyramidal signs since the age of 15 years. MRI findings showed iron deposition in the globus pallidus and substantia nigra on T2 MRI. Whole genome sequencing and RNA sequencing revealed generation of pseudoexon due to inclusion of intronic sequences triggered by an intronic variant that is remote from the exon-intron junction: WDR45 (OMIM #300526) chrX(GRCh37):g.48935143G > C, (NM_007075.4:c.235 + 159C > G). We recapitulated the exonization of intron sequences by a mini-gene assay and further sought antisense oligonucleotide that induce pseudoexon skipping using our recently developed, a dual fluorescent splicing reporter system that encodes two fluorescent proteins, mCherry, a transfection marker designed to facilitate evaluation of exon skipping and split eGFP, a splicing reaction marker. The results showed that the 24-base ASO was the strongest inducer of pseudoexon skipping. Our data presented here have provided supportive evidence for in vivo preclinical studies.

    DOI: 10.1038/s41598-024-56704-z

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  • Gain-of-function MYCN Causes a Megalencephaly-polydactyly Syndrome Manifesting Mirror Phenotypes of Feingold Syndrome. 国際誌

    Yosuke Nishio, Kohji Kato, Frederic Tran Mau-Them, Hiroshi Futagawa, Chloé Quélin, Saori Masuda, Antonio Vitobello, Shiomi Otsuji, Hossam H Shawki, Hisashi Oishi, Christel Thauvin-Robinet, Toshiki Takenouchi, Kenjiro Kosaki, Yoshiyuki Takahashi, Shinji Saitoh

    HGG Advances   4 ( 4 )   100238 - 100238   2023年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis.

    DOI: 10.1016/j.xhgg.2023.100238

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  • Oculofaciocardiodental syndrome caused by a novel BCOR variant 国際誌

    Tomoyo Yamashita, Junko Hotta, Yukiko Jogu, Eri Sakai, Chie Ono, Haruka Bamba, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Kenjiro Kosaki, Tohru Yorifuji, Takashi Hamazaki, Toshiyuki Seto

    Human Genome Variation   10 ( 1 )   18 - 18   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.

    DOI: 10.1038/s41439-023-00244-x

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    その他リンク: https://www.nature.com/articles/s41439-023-00244-x

  • Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences 国際誌

    Mamiko Yamada, Yohei Nitta, Tomoko Uehara, Hisato Suzuki, Fuyuki Miya, Toshiki Takenouchi, Masaru Tamura, Shinya Ayabe, Atsushi Yoshiki, Akiteru Maeno, Yumiko Saga, Tamio Furuse, Ikuko Yamada, Nobuhiko Okamoto, Kenjiro Kosaki, Atsushi Sugie

    European Journal of Medical Genetics   66 ( 8 )   104804 - 104804   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DExH-box helicases are involved in unwinding of RNA and DNA. Among the 16 DExH-box genes, monoallelic variants of DHX16, DHX30, DHX34, and DHX37 are known to be associated with neurodevelopmental disorders. In particular, DHX30 is well established as a causative gene for neurodevelopmental disorders. Germline variants of DHX9, the closest homolog of DHX30, have not been reported until now as being associated with congenital disorders in humans, except that one de novo heterozygous variant, p.(Arg1052Gln) of the gene was identified during comprehensive screening in a patient with autism; unfortunately, the phenotypic details of this individual are unknown. Herein, we report a patients with a heterozygous de novo missense variant, p.(Gly414Arg) of DHX9 who presented with a short stature, intellectual disability, and ventricular non-compaction cardiomyopathy. The variant was located in the glycine codon of the ATP-binding site, G-C-G-K-T. To assess the pathogenicity of these variants, we generated transgenic Drosophila lines expressing human wild-type and mutant DHX9 proteins: 1) the mutant proteins showed aberrant localization both in the nucleus and the cytoplasm; 2) ectopic expression of wild-type protein in the visual system led to the rough eye phenotype, whereas expression of the mutant proteins had minimal effect; 3) overexpression of the wild-type protein in the retina led to a reduction in axonal numbers, whereas expression of the mutant proteins had a less pronounced effect. Furthermore, in a gene-editing experiment of Dhx9 G416 to R416, corresponding to p.(Gly414Arg) in humans, heterozygous mice showed a reduced body size, reduced emotionality, and cardiac conduction abnormality. In conclusion, we established that heterozygosity for a loss-of-function variant of DHX9 can lead to a new neurodevelopmental disorder.

    DOI: 10.1016/j.ejmg.2023.104804

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  • Familial café-au-lait macules associated with in-frame deletion of NF1 p.Met992del mimicking Legius syndrome. 査読 国際誌

    Daisuke Nakato, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki

    Congenital Anomalies   63 ( 2 )   54 - 55   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cga.12506

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  • Vocal Cord Paralysis in Autosomal Dominant Spinal Muscular Atrophy Due to BICD2. 査読 国際誌

    Sachiko Matsui, Sota Iwatani, Naoya Morisada, Toshiki Takenouchi, Seiji Yoshimoto

    Congenital Anomalies   63 ( 2 )   52 - 53   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cga.12500

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  • Diagnosis of Prader-willi Syndrome and Angelman Syndrome by Targeted Nanopore Long-read Sequencing. 査読 国際誌

    Mamiko Yamada, Hironobu Okuno, Nobuhiko Okamoto, Hisato Suzuki, Fuyuki Miya, Toshiki Takenouchi, Kenjiro Kosaki

    European Journal of Medical Genetics   66 ( 2 )   104690 - 104690   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and unmethylated in the paternally derived allele. Both unmethylated and methylated alleles are observed in normal individuals. Only the methylated allele is observed in patients with Prader-Willi syndrome, whereas only the unmethylated allele is observed in those with Angelman syndrome. Hence, detection of aberrant methylation at the differentially methylated region is fundamental to the molecular diagnosis of Prader-Willi syndrome and Angelman syndromes. Traditionally, bisulfite treatment and methylation-sensitive restriction enzyme treatment or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) have been used. We here developed a long-read sequencing assay that can distinguish methylated and unmethylated CpG sites at 15q11.2 by the difference in current intensity generated from nanopore reads. We successfully diagnosed 4 Prader-Willi syndrome patients and 3 Angelman syndrome patients by targeting differentially methylated regions. Concurrent copy number analysis, homozygosity analysis, and structural variant analysis also allowed us to precisely delineate the underlying pathogenic mechanisms, including gross deletion, uniparental heterodisomy, uniparental isodisomy, or imprinting defect. Furthermore, we showed allele-specific methylation in imprinting-related differentially methylated regions on chromosomes 6, 7, 11, 14, and 20 in a normal individual together with 4 Prader-Willi patients and 3 Angelman syndrome patients. Hence, presently reported method is likely to be applicable to the diagnosis of imprinting disorders other than Prader-Willi syndrome and Angelman syndrome as well.

    DOI: 10.1016/j.ejmg.2022.104690

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  • De Novo Non-synonymous DPYSL2 (CRMP2) Variants in Two Patients with Intellectual Disabilities and Documentation of Functional Relevance through Zebrafish Rescue and Cellular Transfection Experiments. 国際誌

    Hisato Suzuki, Simo Li, Tomoharu Tokutomi, Chisen Takeuchi, Miyuki Takahashi, Mamiko Yamada, Hironobu Okuno, Fuyuki Miya, Toshiki Takenouchi, Hironao Numabe, Kenjiro Kosaki, Toshio Ohshima

    Human Molecular Genetics   31 ( 24 )   4173 - 4182   2022年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Collapsin response mediator protein 2 (Crmp2) is an evolutionarily well-conserved tubulin-binding cytosolic protein that plays critical roles in the formation of neural circuitry in model organisms including zebrafish and rodents. No clinical evidence that CRMP2 variants are responsible for monogenic neurogenic disorders in humans presently exists. Here, we describe two patients with de novo non-synonymous variants (S14R and R565C) of CRMP2 and intellectual disability associated with hypoplasia of the corpus callosum. We further performed various functional assays of CRMP2 variants using zebrafish and zebrafish Crmp2 (abbreviated as z-CRMP2 hereafter) and an antisense morpholino oligonucleotide [AMO]-based experimental system in which crmp2-morphant zebrafish exhibit the ectopic positioning of caudal primary (CaP) motor neurons. Whereas the co-injection of wild-type z-CRMP2 mRNA suppressed the ectopic positioning of CaP motor neurons in Crmp2-morphant zebrafish, the co-injection of R566C or S15R, z-CRMP2, which corresponds to R565C and S14R of human CRMP2, failed to rescue the ectopic positioning. Transfection experiments of zebrafish or rat Crmp2 using plasmid vectors in HeLa cells, with or without a proteasome inhibitor, demonstrated that the expression levels of mutant Crmp2 protein encoded by R565C and S14R CRMP2 variants were decreased, presumably because of increased degradation by proteasomes. When we compared CRMP2-tubulin interactions using co-immunoprecipitation and cellular localization studies, the R565C and S14R mutations weakened the interactions. These results collectively suggest that the CRMP2 variants detected in the present study consistently led to the loss-of-function of CRMP2 protein and support the notion that pathogenic variants in CRMP2 can cause intellectual disabilities in humans.

    DOI: 10.1093/hmg/ddac166

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  • De Novo Non-synonymous CTR9 Variants Are Associated with Motor Delay and Macrocephaly: Human Genetic and Zebrafish Experimental Evidence. 国際誌

    Hisato Suzuki, Kana Aoki, Kenji Kurosawa, Kazuo Imagawa, Tatsuyuki Ohto, Mamiko Yamada, Toshiki Takenouchi, Kenjiro Kosaki, Tohru Ishitani

    Human Molecular Genetics   31 ( 22 )   3846 - 3854   2022年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.

    DOI: 10.1093/hmg/ddac136

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  • Neuropsychiatric Systemic Lupus Erythematosus in a Girl with Neurocutaneous Melanosis Caused by a Somatic Mutation in NRAS. 国際誌

    Tomohiro Inoguchi, Toshiki Takenouchi, Fumito Yamazaki, Yasushi Kondo, Hiroto Mitamura, Kenjiro Kosaki, Takao Takahashi

    Rheumatology (Oxford, England)   61 ( 8 )   e224-e226   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/rheumatology/keac130

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  • Deciphering Complex Rearrangements at the Breakpoint of an Apparently Balanced Reciprocal Translocation T(4:18)(q31;q11.2)dn and at a Cryptic Deletion: Further Evidence of TLL1 as a Causative Gene for Atrial Septal Defect. 国際誌

    Mamiko Yamada, Hisato Suzuki, Fuyuki Miya, Toshiki Takenouchi, Kenjiro Kosaki

    American Journal of Medical Genetics. Part a   188 ( 8 )   2472 - 2478   2022年8月

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    記述言語:英語  

    When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an "apparently balanced" de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7-Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Further analysis using a nanopore long-read sequencer showed complex rearrangements on both derivative chromosomes 4 and 18 and the deleted chromosome 2. First, the TLL1 locus, which is associated with atrial septal defect, was disrupted by the rearrangement involving chromosome 4. Second, the deleted interval at 2q31 included the entire HOXD cluster, the deletion of which is known to cause toe syndactyly, and the DLX1 and DLX2 loci, which are responsible for cleft lip and palate. Among the haplo-sensitive genes within the deleted interval on 2q31, only the RAPGEF4 gene is known to be associated with an autistic phenotype. Hence, most of the clinical features of the patient could be ascribed to specific genomic rearrangements. We have shown the effectiveness of long-read sequencing in defining, in detail, the likely effects of an apparently balanced translocation and cryptic deletion. The results of the present analysis suggest the possibility of phenotypic prediction through a detailed analysis of structural abnormalities, including balanced translocations and deletions.

    DOI: 10.1002/ajmg.a.62777

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  • Precocious Puberty in a Case of Simpson-golabi-behmel Syndrome with a De Novo 240-kb Deletion Including GPC3. 国際誌

    Keisuke Watanabe, Atsuko Noguchi, Ikuko Takahashi, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Tsutomu Takahashi

    Human Genome Variation   9 ( 1 )   23 - 23   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Here, we report a Japanese patient with Simpson-Golabi-Behmel syndrome involving a de novo 240-kb deletion including a part of GPC3. The patient showed pre- and postnatal macrosomia associated with coarse face, macrocephaly, supernumerary nipples, and cryptorchidism and characteristically presented with precocious puberty, mostly evaluated as advanced pubertal age of 15 years at the chronological age of 11.5 years.

    DOI: 10.1038/s41439-022-00196-8

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  • Phenotypic Overlap Between Cardioacrofacial Dysplasia-2 and Oral-facial-digital Syndrome. 国際誌

    Mamiko Yamada, Hisato Suzuki, Hiroshi Futagawa, Toshiki Takenouchi, Fuyuki Miya, Hiroshi Yoshihashi, Kenjiro Kosaki

    European Journal of Medical Genetics   65 ( 6 )   104512 - 104512   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Oral-facial digital (OFD) syndrome is characterized by abnormalities of the face (hypertelorism and low set-ears), oral cavity (multiple frenula, lingual hamartoma, or lobulated tongue) and extremities (postaxial polydactyly). At least 19 genes have been implicated in the development of OFD syndrome. Herein, we report the case a 13-year-old patient with atrioventricular septal defect, moderate intellectual disability, epilepsy, and features of OFD, including multiple oral frenula, and postaxial polydactyly of the hands and feet. The patient had a de novo heterozygous variant in PRKACB: chr1(GRCh37):g.84700915T > C, c.1124T > C (NM_182948.4), p.(Phe375Ser). To date, four patients with pathogenic monoallelic variants in PRKACB have been reported, and the condition associated with these variants is referred to as Cardioacrofacial dysplasia-2 (CAFD2, MIM619143). Previously reported features of this condition include congenital heart disease (e.g., atrioventricular septal defect) and postaxial polydactyly, and two of the patients had multiple oral frenula. We suggest that a significant phenotypic overlap exists between CAFD2 and OFD syndrome, in that these patients especially share the features of postaxial polydactyly and multiple oral frenula. The phenotypic similarity between patients with CAFD2 and classic OFD syndrome with an OFD1 variant might be explained by the recent in vitro experimental finding that a protein kinase A subunit encoded by PRKACB directly phosphorylates the OFD1 protein. From the standpoint of genetic counseling, OFD syndrome type1, the prototypic form of OFD, exhibits an X-linked dominant inheritance pattern, whereas other forms of OFD syndrome exhibit an autosomal recessive inheritance pattern. Recognition of CAFD2 as a differential diagnosis or forme fruste of OFD syndrome suggests that an autosomal dominant pattern of inheritance should also be considered during genetic counseling.

    DOI: 10.1016/j.ejmg.2022.104512

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  • Mutation of PTPN11 (Encoding SHP-2) Promotes MEK Activation and Malignant Progression in Neurofibromin-Deficient Cells in a Manner Sensitive to BRAP Mutation. 国際誌

    Ritsuko Harigai, Ryo Sato, Chikako Hirose, Toshiki Takenouchi, Kenjiro Kosaki, Takanori Hirose, Hideyuki Saya, Yoshimi Arima

    Cancers   14 ( 10 )   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, PTPN11, encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of PTPN11 and NF1 mutations induces the pathological activation of the RAS pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of BRAP, which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by BRAP (G370A) were not detected in NF1-intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by BRAP (G370A) may serve as a basis for the development of new treatment strategies for NF1.

    DOI: 10.3390/cancers14102377

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  • Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations. 国際誌

    Hisato Suzuki, Masatoshi Nozaki, Hiroshi Yoshihashi, Kazuo Imagawa, Daigo Kajikawa, Mamiko Yamada, Yu Yamaguchi, Naoya Morisada, Mayuko Eguchi, Shoko Ohashi, Shinsuke Ninomiya, Toshiyuki Seto, Tomoharu Tokutomi, Mariko Hida, Katsuaki Toyoshima, Masatoshi Kondo, Ayano Inui, Kenji Kurosawa, Rika Kosaki, Yushi Ito, Nobuhiko Okamoto, Kenjiro Kosaki, Toshiki Takenouchi

    The Journal of pediatrics   244   38 - 48   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. STUDY DESIGN: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The subjects underwent medical exome, whole exome, or whole genome sequencing during the first tier of testing. Subjects with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management evaluated through contacting primary care physicians. RESULTS: Of the 85 subjects, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 subjects), followed by renal (60%, 3/5 subjects), and neurological phenotypes (58%, 14/24 subjects). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 subjects with molecular diagnosis, 20/41 (49%) had change in the clinical management. CONCLUSIONS: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurological phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the subjects. The resulting molecular diagnoses had a significant impact on clinical management.

    DOI: 10.1016/j.jpeds.2022.01.033

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  • The p.Thr395Met Missense Variant of NFIA Found in a Patient with Intellectual Disability Is a Defective Variant. 査読 国際誌

    Yurie Ogura, Tomoko Uehara, Kota Ujibe, Hiroshi Yoshihashi, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Hiromi Hirata

    American Journal of Medical Genetics. Part a   188 ( 4 )   1184 - 1192   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nuclear factor one A (NFIA) is a transcription factor that regulates the development of the central nervous system. Haploinsufficiency of the NFIA gene causes NFIA-related disorder, which includes brain abnormalities and intellectual disability, with or without urinary tract defects. Intragenic deletions, nonsense variants, frameshift variants, and missense variants in one allele of the NFIA gene have been reported to cause various neurological and urogenital symptoms. Here we report a 10-year-old male patient with developmental delay, coarctation of the aorta, and distinctive facial features. Exome analysis identified a rare de novo heterozygous missense variant p.Thr395Met in NFIA. We employed zebrafish as a model organism in our NFIA analysis and found that nfia-/- zebrafish initially showed a loss of commissural axons in the brain, and eventually underwent growth retardation resulting in premature death. Impairment of the commissural neurons in nfia-/- zebrafish embryos could be restored by the expression of wild-type human NFIA protein, but not of mutant human protein harboring the p.Thr395Met substitution, indicating that this variant affects the function of NFIA protein. Taken together, we suggest that the p.Thr395Met allele in the NFIA gene is relevant to the pathogenesis of NFIA-related disorder.

    DOI: 10.1002/ajmg.a.62638

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  • Vanishing basal ganglia in ATP1A3-related polymicrogyria. 国際誌

    Eri Ogawa, Yuri Sakaguchi, Mikako Enokizono, Hiroshi Yoshihashi, Mamiko Yamada, Hisato Suzuki, Kenjiro Kosaki, Sahoko Miyama, Toshiki Takenouchi

    American journal of medical genetics. Part A   188 ( 2 )   665 - 667   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.62531

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  • The novel and recurrent variants in exon 31 of CREBBP in Japanese patients with Menke-Hennekam syndrome. 国際誌

    Eriko Nishi, Toshiki Takenouchi, Fuyuki Miya, Tomoko Uehara, Kumiko Yanagi, Yuiko Hasegawa, Kimiko Ueda, Seiji Mizuno, Tadashi Kaname, Kenjiro Kosaki, Nobuhiko Okamoto

    American journal of medical genetics. Part A   188 ( 2 )   446 - 453   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder caused by the heterozygous variants in exon 30 or 31 of CREBBP (CREB binding protein) gene mapped on 16p13.3. It is characterized by psychomotor delay, variable impairment of intellectual disability (ID), feeding difficulty, autistic behavior, hearing impairment, short stature, microcephaly, and facial dysmorphisms. The CREBBP loss-of-function variants cause Rubinstein-Taybi syndrome-1 (RSTS1). The function of CREBBP leading to MKHK1 has not been clarified so far, and the phenotype of MKHK1 significantly differs from that of RSTS1. We examined six patients with de novo pathogenic variants affecting the last exon of CREBBP, and they shared the clinical features of MKHK1. This study revealed that one frameshift and three nonsense variants of CREBBP cause MKHK1, and inferred that the nonsense variants of the last exon could further help in the elucidation of the etiology of MKHK1.

    DOI: 10.1002/ajmg.a.62533

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  • Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy. 国際誌

    Yuka Murofushi, Itaru Hayakawa, Yuichi Abe, Tatsuyuki Ohto, Kei Murayama, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Masaya Kubota

    Neuropediatrics   53 ( 1 )   65 - 68   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

    DOI: 10.1055/s-0041-1732446

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  • Pro108Ser Mutation of SARS-CoV-2 3CLpro Reduces the Enzyme Activity and Ameliorates the Clinical Severity of COVID-19. 国際誌

    Kodai Abe, Yasuaki Kabe, Susumu Uchiyama, Yuka W Iwasaki, Hirotsugu Ishizu, Yoshifumi Uwamino, Toshiki Takenouchi, Shunsuke Uno, Makoto Ishii, Takahiro Maruno, Masanori Noda, Mitsuru Murata, Naoki Hasegawa, Hideyuki Saya, Yuko Kitagawa, Koichi Fukunaga, Masayuki Amagai, Haruhiko Siomi, Makoto Suematsu, Kenjiro Kosaki

    Scientific Reports   12 ( 1 )   1299 - 1299   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.

    DOI: 10.1038/s41598-022-05424-3

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  • Long-term Course of Early Onset Developmental and Epileptic Encephalopathy Associated with 2q24.3 Microduplication. 国際誌

    Takuya Masuda, Hitoshi Osaka, Naomi Tsuchida, Satoko Miyatake, Kou Nishimura, Toshiki Takenouchi, Takao Takahashi, Naomichi Matsumoto, Takanori Yamagata

    Epilepsy & Behavior Reports   19   100547 - 100547   2022年

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    記述言語:英語  

    Copy number variations (CNVs) have been related to developmental and epileptic encephalopathy (DEE). The 2q24.3 region includes a cluster of genes for voltage-gated sodium channels (SCN) and CNVs in this region cause DEE. However, the long-term course of DEE with a 2q24.3 duplication has not been described. A 20-year-old female developed epileptic encephalopathy in early infancy that was resistant to various antiseizure medications. Her seizures disappeared after starting vitamin B6 therapy. Therefore, her epilepsy was considered pyridoxine-dependent epilepsy. At 16 years old, whole exome sequencing revealed a 2q24.3 microduplication including SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A. Quantitative PCR detected an increased copy number of 1.3 Mb on 2q24.3 involving these genes, but no gene mutation accounting for pyridoxine-dependent epilepsy. Considering that with this duplication she was reported to be seizure-free after infancy, she was able to be off antiseizure medications including vitamin B6. Our case involvingdrug-resistant epilepsy in early infancy had no recurrent seizures during long-term follow up. Detecting CNVs using whole exome sequencing data was useful to identify a 2q24.3 duplication unassociated with pyridoxine-dependent epilepsy, leading to cessation of unnecessary medications.

    DOI: 10.1016/j.ebr.2022.100547

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  • 乳児期早期に急性肝不全の経過を示し、網羅的遺伝子解析を契機に診断した若年性骨髄単球性白血病

    今川 和生, 森田 篤志, 田川 学, 須磨崎 亮, 梶川 大悟, 長友 公美絵, 福島 紘子, 鈴木 寿人, 武内 俊樹, 小崎 健次郎, 高田 英俊

    日本小児栄養消化器肝臓学会雑誌   35 ( 2 )   89 - 89   2021年12月

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    記述言語:日本語   出版者・発行元:(一社)日本小児栄養消化器肝臓学会  

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  • Decisive evidence of direct effect of ACTH treatment in West syndrome: A case report. 国際誌

    Marie Sasaki, Toshiki Takenouchi, Yuri Sakaguchi, Takao Takahashi

    Seizure   91   49 - 51   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.seizure.2021.05.016

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  • Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles. 国際誌

    Tomoko Uehara, Rikako Sanuki, Yurie Ogura, Atsushi Yokoyama, Takeshi Yoshida, Hiroshi Futagawa, Hiroshi Yoshihashi, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Kohei Matsubara, Hiromi Hirata, Kenjiro Kosaki, Toshiyuki Takano-Shimizu

    American journal of medical genetics. Part A   185 ( 7 )   2084 - 2093   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.

    DOI: 10.1002/ajmg.a.62226

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  • Noonan syndrome-like phenotype in a patient with heterozygous ERF truncating variant. 国際誌

    Mamiko Yamada, Michinori Funato, Goro Kondo, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Yoshiaki Sakamoto, Kenjiro Kosaki

    Congenital anomalies   61 ( 6 )   226 - 230   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Craniosynostosis is caused by abnormalities of multiple signaling pathways, including excessive RAS signaling. Recently, a truncating variant in ETS2 repressor factor (ERF), a negative transcriptional regulator of the RAS pathway, was shown to be associated with craniosynostosis. Here, we report a 10-year-old male patient with a heterozygous nonsense mutation, p.Arg183*, in ERF who exhibited craniosynostosis with Noonan syndrome-like phenotypes. In consideration that loss-of-function variants in ERF would result in excessive RAS signaling and RASopathy phenotypes, we propose that ERF may represent a causative gene for Noonan syndrome. Since preceding studies on ERF mutations dealt with patients who were ascertained because of craniosynostosis, further studies are needed to evaluate whether patients with variants in ERF can present with Noonan syndrome-like features without craniosynostosis.

    DOI: 10.1111/cga.12435

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  • Identification of B.1.346 Lineage of SARS-CoV-2 in Japan: Genomic Evidence of Re-entry of Clade 20C.

    Kodai Abe, Takako Shimura, Toshiki Takenouchi, Yuka W Iwasaki, Hirotsugu Ishizu, Yoshifumi Uwamino, Shunsuke Uno, Jun Gotoh, Natsuo Tachikawa, Yuriko Takeuchi, Junpei Katayama, Hiroyuki Nozaki, Susumu Fujii, Shikou Seki, Morio Nakamura, Kazuhiro Uda, Takahiko Misumi, Jun Ishihara, Kenichiro Yamada, Toshio Kanai, Shinji Murai, Kazuhiro Araki, Tamotsu Ebihara, Haruhiko Siomi, Naoki Hasegawa, Yuko Kitagawa, Masayuki Amagai, Makoto Suematsu, Kenjiro Kosaki

    The Keio journal of medicine   70 ( 2 )   44 - 50   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.

    DOI: 10.2302/kjm.2021-0005-OA

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  • A Japanese adult and two girls with NEDMIAL caused by de novo missense variants in DHX30. 国際誌

    Kimiko Ueda, Atsushi Araki, Atsushi Fujita, Naomichi Matsumoto, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Nobuhiko Okamoto

    Human genome variation   8 ( 1 )   24 - 24   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lessel et al. reported a novel neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) in 12 individuals and identified six different de novo heterozygous missense variants in DHX30. The other clinical features included muscular hypotonia, feeding difficulties, brain anomalies, autistic features, sleep disturbances, and joint hypermobility. We report a Japanese adult with a novel missense variant and two girls with de novo missense variants in DHX30.

    DOI: 10.1038/s41439-021-00155-9

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  • Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. 国際誌

    Norine Voisin, Rhonda E Schnur, Sofia Douzgou, Susan M Hiatt, Cecilie F Rustad, Natasha J Brown, Dawn L Earl, Boris Keren, Olga Levchenko, Sinje Geuer, Sarah Verheyen, Diana Johnson, Yuri A Zarate, Miroslava Hančárová, David J Amor, E Martina Bebin, Jasmin Blatterer, Alfredo Brusco, Gerarda Cappuccio, Joel Charrow, Nicolas Chatron, Gregory M Cooper, Thomas Courtin, Elena Dadali, Julien Delafontaine, Ennio Del Giudice, Martine Doco, Ganka Douglas, Astrid Eisenkölbl, Tara Funari, Giuliana Giannuzzi, Ursula Gruber-Sedlmayr, Nicolas Guex, Delphine Heron, Øystein L Holla, Anna C E Hurst, Jane Juusola, David Kronn, Alexander Lavrov, Crystle Lee, Séverine Lorrain, Else Merckoll, Anna Mikhaleva, Jennifer Norman, Sylvain Pradervand, Darina Prchalová, Lindsay Rhodes, Victoria R Sanders, Zdeněk Sedláček, Heidelis A Seebacher, Elizabeth A Sellars, Fabio Sirchia, Toshiki Takenouchi, Akemi J Tanaka, Heidi Taska-Tench, Elin Tønne, Kristian Tveten, Giuseppina Vitiello, Markéta Vlčková, Tomoko Uehara, Caroline Nava, Binnaz Yalcin, Kenjiro Kosaki, Dian Donnai, Stefan Mundlos, Nicola Brunetti-Pierri, Wendy K Chung, Alexandre Reymond

    American journal of human genetics   108 ( 5 )   857 - 873   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

    DOI: 10.1016/j.ajhg.2021.04.001

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  • Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants. 国際誌

    Mamiko Yamada, Masae Ono, Tomohiro Ishii, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki

    American journal of medical genetics. Part A   185 ( 6 )   1836 - 1840   2021年3月

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    記述言語:英語  

    Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.

    DOI: 10.1002/ajmg.a.62152

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  • Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations. 国際誌

    Katsuya Hirata, Nobuhiko Okamoto, Chihiro Ichikawa, Shouta Inoue, Masatoshi Nozaki, Kimihiko Banno, Toshiki Takenouchi, Hisato Suzuki, Kenjiro Kosaki

    American journal of medical genetics. Part A   185 ( 3 )   866 - 870   2021年3月

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    記述言語:英語  

    Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl-tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis-like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole-exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

    DOI: 10.1002/ajmg.a.62012

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  • Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome. 査読 国際誌

    Toshiki Takenouchi, Kazuki Kodo, Fumito Yamazaki, Hirofumi Nakatomi, Kenjiro Kosaki

    American journal of medical genetics. Part A   185 ( 3 )   999 - 1003   2021年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet-derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular-type Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow-up examinations.

    DOI: 10.1002/ajmg.a.62027

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  • Fork-shaped mandibular incisors as a novel phenotype of LRP5-associated disorder. 国際誌

    Mamiko Yamada, Kazumi Kubota, Atsuro Uchida, Tatsuhiko Yagihashi, Masahito Kawasaki, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Hiroshi Kurosaka, Kenjiro Kosaki

    American journal of medical genetics. Part A   185 ( 5 )   1544 - 1549   2021年2月

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    記述言語:英語  

    The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14-year-old patient with a de novo non-synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork-like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss-of-function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss-of-function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant-negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

    DOI: 10.1002/ajmg.a.62132

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  • Assessment of long-term quality of life in patients with syndromic craniosynostosis. 国際誌

    Yoshiaki Sakamoto, Toshiki Takenouchi, Tomoru Miwa, Kazuo Kishi

    Journal of plastic, reconstructive & aesthetic surgery : JPRAS   74 ( 2 )   336 - 340   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Several studies have analyzed the long-term stability of cranioplasty and midface distraction in patients with craniosynostosis; however, few studies have investigated long-term quality of life (QOL) and complications in adults with syndromic craniosynostosis. This study aimed to investigate the QOL (social, physical, and psychosocial) of patients with adult syndromic craniosynostosis. Patients aged ≥20 years with syndromic craniosynostosis, who were surgically treated at a single craniofacial institution, were included in this study. We investigated everyday inconvenience (using the World Health Organization Disability Assessment Schedule questionnaire), any ongoing treatment, marital status, and number of children. Totally, 18 patients aged 22-48 years (mean: 31.4 ± 9.2 years) answered the questionnaire (Crouzon syndrome, 9; Apert syndrome, 5; Pfeiffer syndrome, 4). Of these, only one Crouzon syndrome patient was married; she was also the only one with a child. Apert syndrome patients were found to have difficulty in understanding, communication, and self-care because of their mental retardation and hand and foot handicaps; however, their participation in society was the most aggressive. In contrast, Crouzon syndrome patients had especially poor participation in society. In all patients, any ongoing hospital treatment was due to ophthalmological conditions. Crouzon syndrome patients have extremely poor QOL; the absence of mental retardation and hand and foot handicaps forces them to live in mainstream society, for which they are emotionally ill-equipped. It is necessary to treat these patients without any residual deformity to provide psychological support and to create an accepting society.

    DOI: 10.1016/j.bjps.2020.08.102

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  • Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3. 国際誌

    Maiko Hatano, Hiroko Fukushima, Tatsuyuki Ohto, Yuichi Ueno, Saki Saeki, Takashi Enokizono, Ryuta Tanaka, Mai Tanaka, Kazuo Imagawa, Yu Kanai, Mitsuhiro Kato, Hiroshi Shiraku, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki, Hidetoshi Takada

    American journal of medical genetics. Part A   185 ( 4 )   1113 - 1119   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

    DOI: 10.1002/ajmg.a.62084

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  • Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants 国際誌

    Takenori Tozawa, Akira Nishimura, Tamaki Ueno, Akane Shikata, Yoshihiro Taura, Takeshi Yoshida, Naoko Nakagawa, Takahito Wada, Shinji Kosugi, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki, Tomohiro Chiyonobu

    HUMAN GENOME VARIATION   8 ( 1 )   4 - 4   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41439-021-00136-y

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  • Multiple Introductions of SARS-CoV-2 B.1.1.214 Lineages from Mainland Japan Preceded the Third Wave of the COVID-19 Epidemic in Hokkaido. 国際誌

    Takako Shimura, Kodai Abe, Toshiki Takenouchi, Mamiko Yamada, Hisato Suzuki, Makoto Suematsu, Sho Nakakubo, Keisuke Kamada, Satoshi Konno, Takanori Teshima, Kenjiro Kosaki

    Travel Medicine and Infectious Disease   44   102210 - 102210   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The third wave of the COVID-19 epidemic in the island of Hokkaido, the second largest island in Japan, began abruptly in October 2020. METHODS: We conducted a phylodynamic analysis of the SARS-CoV-2 genome sequences obtained from tertiary medical centers in the Greater Tokyo Area and Sapporo, the largest city in the island of Hokkaido, and genome sequences published by GISAID, an international SARS-CoV-2 genome database. We also analyzed the statistics on the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 versus 2020. RESULTS: At least eight sub-lineages belonging to the B.1.1.214 lineage were introduced to the island of Hokkaido from the island of Honshu, the mainland of Japan from late July to November 2020, during the governmental travel promotion program. Five of the eight sub-lineages originated from the Greater Tokyo Area. Comparison of the monthly ratios of the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 and 2020 revealed that the highest value occurred in October 2020. CONCLUSION: We contend that the Japanese governmental travel promotion program contributed to the introduction of the B.1.1.214 sub-lineages from the main island of Honshu to the island of Hokkaido, and drove the third wave in Hokkaido, even if we are unable to establish the causality.

    DOI: 10.1016/j.tmaid.2021.102210

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  • Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures. 国際誌

    Hisato Suzuki, Mie Inaba, Mamiko Yamada, Tomoko Uehara, Toshiki Takenouchi, Seiji Mizuno, Kenjiro Kosaki, Motomichi Doi

    American journal of medical genetics. Part A   185 ( 4 )   1182 - 1186   2020年12月

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    記述言語:英語  

    The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.

    DOI: 10.1002/ajmg.a.62054

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  • Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis. 国際誌

    Yuri Sakaguchi, Hiroshi Yoshihashi, Tomoko Uehara, Sahoko Miyama, Kenjiro Kosaki, Toshiki Takenouchi

    American journal of medical genetics. Part A   185 ( 3 )   884 - 888   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.

    DOI: 10.1002/ajmg.a.62020

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  • GNAO1 mutation-related severe involuntary movements treated with gabapentin. 国際誌

    Manami Akasaka, Atsushi Kamei, Sachiko Tanifuji, Maya Asami, Jun Ito, Kanako Mizuma, Kotaro Oyama, Tomoharu Tokutomi, Kayono Yamamoto, Akimune Fukushima, Toshiki Takenouchi, Tomoko Uehara, Hisato Suzuki, Kenjiro Kosaki

    Brain & development   43 ( 4 )   576 - 579   2020年12月

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    記述言語:英語  

    BACKGROUND: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators. CASE: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely. CONCLUSION: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.

    DOI: 10.1016/j.braindev.2020.12.002

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  • Role of chimeric transcript formation in the pathogenesis of birth defects. 国際誌

    Mamiko Yamada, Hisato Suzuki, Akiko Watanabe, Tomoko Uehara, Toshiki Takenouchi, Seiji Mizuno, Kenjiro Kosaki

    Congenital anomalies   61 ( 3 )   76 - 81   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA-seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: 1) The first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA-seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436-kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat-Wilson syndrome was made. 2) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA-seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186-kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk-Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA-seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion. This article is protected by copyright. All rights reserved.

    DOI: 10.1111/cga.12400

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  • Clinical Utility of SARS-CoV-2 Whole Genome Sequencing in Deciphering Source of Infection. 査読 国際誌

    Toshiki Takenouchi, Yuka W Iwasaki, Sei Harada, Hirotsugu Ishizu, Yoshifumi Uwamino, Shunsuke Uno, Asami Osada, Kodai Abe, Naoki Hasegawa, Mitsuru Murata, Toru Takebayashi, Koichi Fukunaga, Hideyuki Saya, Yuko Kitagawa, Masayuki Amagai, Haruhiko Siomi, Kenjiro Kosaki

    The Journal of hospital infection   107   40 - 4   2020年10月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    COVID-19 caused by SARS-CoV-2 is a worldwide problem. From the standpoint of hospital infection control, determining the source of infection is critical. We conducted the present study to evaluate the efficacy of using whole genome sequencing to determine the source of infection in hospitalized patients who do not have a clear infectious contact history. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary hospital. Whole viral genome sequencing distinguished the two clusters according to the viral haplotype. However, the source of infection was unclear in 14 patients with COVID-19 who were clinically unlinked to clusters #1 or #2. These patients, who had no clear history of infectious contact within the hospital ("undetermined source of infection"), had haplotypes similar to those in cluster #2 but did not have two of the mutations used to characterize cluster #2, suggesting that these 14 cases of "undetermined source of infection" were not derived from cluster #2. Whole viral genome sequencing can be useful for confirming that sporadic COVID-19 cases with an undetermined source of infection are indeed not part of clusters at the institutional level.

    DOI: 10.1016/j.jhin.2020.10.014

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  • Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants. 査読 国際誌

    Tomoko Uehara, Kota Abe, Masayuki Oginuma, Shizuka Ishitani, Hiroshi Yoshihashi, Nobuhiko Okamoto, Toshiki Takenouchi, Kenjiro Kosaki, Tohru Ishitani

    Scientific reports   10 ( 1 )   17575 - 17575   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.

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  • A Case of Pulmonary Veno-occlusive Disease Following Hepatic Veno-occlusive Disease After Autologous Hematopoietic Stem Cell Transplantation for Neuroblastoma. 国際誌

    Kyohei Isshiki, Haruko Shima, Fumito Yamazaki, Toshiki Takenouchi, Hiroyuki Shimada

    Journal of pediatric hematology/oncology   42 ( 7 )   e677-e679   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension that is usually difficult to diagnose and is refractory to conservative treatment. PVOD can occur in connection with high-dose chemotherapy or hematopoietic stem cell transplantation, similar to hepatic veno-occlusive disease (HVOD). Here, we present a case of neuroblastoma with PVOD following HVOD after high-dose chemotherapy that was resolved with conservative treatment. Respiratory symptoms or edema after HVOD may suggest PVOD, and prompt diagnosis on high-resolution computed tomography will result in a favorable prognosis.

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  • Learning disability and myoclonic epilepsy associated with apparently synonymous but splice-disrupting JMJD1C variant that led to 21 bp deletion of the transcript. 国際誌

    Mamiko Yamada, Tatsuyuki Sokoda, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Tatsuhiko Yagihashi, Yoshihiro Maruo, Kenjiro Kosaki

    American journal of medical genetics. Part A   182 ( 12 )   3064 - 3067   2020年9月

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    記述言語:英語  

    DOI: 10.1002/ajmg.a.61892

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  • Diagnostic utility of integrated analysis of exome and transcriptome: Successful diagnosis of Au-Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities. 国際誌

    Mamiko Yamada, Yuichi Shiraishi, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Chihiro Abe-Hatano, Kenji Kurosawa, Kenjiro Kosaki

    Molecular genetics & genomic medicine   8 ( 9 )   e1364   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor-acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease-causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented. METHOD: We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8 years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears. RESULT: A SAVNet analysis showed that a heterozygous intronic variant located at the -10 position of exon 5 of the HNRNPK gene on chromosome 9 created a new splice acceptor sequence "ag" and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu-Leu-Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au-Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability. CONCLUSION: The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome-transcriptome analysis in clinical settings.

    DOI: 10.1002/mgg3.1364

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  • Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome. 国際誌

    Mamiko Yamada, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki

    American journal of medical genetics. Part A   182 ( 11 )   2709 - 2714   2020年8月

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    記述言語:英語  

    The PUF60 gene encodes a ubiquitously expressed essential splicing factor that is recruited to the U2snRNA complex. The complex binds to the 3' splice site of exons in specific target genes and regulates the inclusion or exclusion of such exons. Recently, pathogenic variants of PUF60 have been shown to cause a relatively specific and potentially recognizable pattern of malformation referred to as Verheij syndrome. Here, we report a 12-year-old female patient with a de novo mutation in PUF60 whose phenotype was representative of the milder end of the phenotypic spectrum of Verheij syndrome; the de novo mutation was a frameshift mutation p.(Ser558Cysfs*21) that resulted in the addition of 21 extra amino acids at the carboxy end of the protein. Among the frequent features of Verheij syndrome, the patient exhibited coloboma, cervical spinal segmentation defects, and borderline intellectual functioning, but lacked cardiac abnormalities, deafness, and urogenital abnormalities. The results of RNA analysis using peripheral blood showed the escape of the mutant allele from nonsense-mediated mRNA decay, possibly accounting for the mild phenotype in the presently reported patient. Based on our clinical observations, we inferred that two embryologic processes, closure of the ocular plate and cervical spinal segmentation, are particularly susceptible to deficient PUF60-mediated splicing regulation, compared with other embryogenetic processes leading to the central nervous system, heart, ear, and kidney.

    DOI: 10.1002/ajmg.a.61816

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  • Parallel detection of single nucleotide variants and copy number variants with exome analysis: Validation in a cohort of 700 undiagnosed patients. 国際誌

    Hisato Suzuki, Mamiko Yamada, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki

    American journal of medical genetics. Part A   182 ( 11 )   2529 - 2532   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Copy number variants (CNVs) are significant causes of rare and undiagnosed diseases. Parallel detection of single nucleotide variants (SNVs) and CNVs with exome analysis, if feasible, would shorten the diagnostic closure in a timely manner. We validated such "parallel" approach through a cohort study of 791 undiagnosed patients. In addition to routine exome analysis, we applied an innovative algorithm EXCAVATOR2 which enhances sensitivity by paradoxically exploiting read depth data that covers nonexonic regions where baits were not originally intended to hybridize. About 48 patients had copy number variations, 42 deletions, and 6 duplications with a resolution of 0.51-14.7 mega base pairs. Importantly from a clinical standpoint, we identified three patients with "dual diagnosis" due to concurrent pathogenic CNV and SNV. We suggest "hitting two birds with one stone" approach to exome data is an efficient strategy in deciphering undiagnosed patients and may well be considered as a first-tier genetic test.

    DOI: 10.1002/ajmg.a.61822

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  • Hypercoagulopathy Associated With Uniparental Disomy of Chromosome 2. 査読 国際誌

    Toshiki Takenouchi, Takayuki Yamada, Yusuke Kashiwagi, Yu Yamaguchi, Tomoko Uehara, Kenjiro Kosaki

    Journal of pediatric hematology/oncology   42 ( 5 )   370 - 371   2020年6月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1097/MPH.0000000000001834

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  • Consecutive medical exome analysis at a tertiary center: Diagnostic and health-economic outcomes. 査読 国際誌

    Rika Kosaki, Masaya Kubota, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki

    American journal of medical genetics. Part A   182 ( 7 )   1601 - 1607   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The utility of whole exome analysis has been extensively demonstrated in research settings, but its clinical utility as a first-tier genetic test has not been well documented from diagnostic and health economic standpoints in real-life clinical settings. We performed medical exome analyses focusing on a clinically interpretable portion of the genome (4,813 genes) as a first-tier genetic test for 360 consecutive patients visiting a genetics clinic at a tertiary children's hospital in Japan, over a 3-year period. Bioinformatics analyses were conducted using standard software. A molecular diagnosis was made in 171 patients involving a total of 107 causative genes. Among these 107 causative genes, 57 genes were classified as genes with potential organ-specific interventions and management strategies. Clinically relevant results were obtained in 26% of the total cohort and 54% of the patients with a definitive molecular diagnosis. Performing the medical exome analysis at the time of the initial visit to the tertiary center, rather than after visits to pertinent specialists, brain MRI examination, and G-banded chromosome testing, would have reduced the financial cost by 197 euros according to retrospective calculation under multiple assumption. The present study demonstrated a high diagnostic yield (47.5%) for singleton medical exome analysis as a first-tier test in a real-life setting. Medical exome analysis yielded clinically relevant information in a quarter of the total patient cohort. The application of genomic testing during the initial visit to a tertiary medical center could be a rational approach to the diagnosis of patients with suspected genetic disorders.

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  • Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1 査読 国際誌

    Mamiko Yamada, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Ayano Inui, Masako Ikemiyagi, Isamu Kamimaki, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   182 ( 7 )   1631 - 1636   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.61598

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  • Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis. 査読 国際誌

    Tomoko Uehara, Mamiko Yamada, Shuichiro Umetsu, Hiroshi Nittono, Hisato Suzuki, Tomoo Fujisawa, Toshiki Takenouchi, Ayano Inui, Kenjiro Kosaki

    The Journal of pediatrics   221   251 - 254   2020年4月

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    記述言語:英語  

    We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.

    DOI: 10.1016/j.jpeds.2020.01.064

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  • Novel ARX mutation identified in infantile spasm syndrome patient 査読 国際誌

    Yohei Takeshita, Tatsuyuki Ohto, Takashi Enokizono, Mai Tanaka, Hisato Suzuki, Hiroko Fukushima, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki, Hidetoshi Takada

    HUMAN GENOME VARIATION   7 ( 1 )   9 - 9   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41439-020-0094-2

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  • IFT172 as the 19th gene causative of oral-facial-digital syndrome. 査読 国際誌

    Mamiko Yamada, Tomoko Uehara, Hisato Suzuki, Toshiki Takenouchi, Hiroyuki Fukushima, Naoya Morisada, Kenta Tominaga, Motohiro Onoda, Kenjiro Kosaki

    American journal of medical genetics. Part A   179 ( 12 )   2510 - 2513   2019年12月

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    記述言語:英語  

    DOI: 10.1002/ajmg.a.61373

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  • Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta. 国際誌

    Toshiki Takenouchi, Hironobu Okuno, Kenjiro Kosaki

    American journal of medical genetics. Part C, Seminars in medical genetics   181 ( 4 )   650 - 657   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

    DOI: 10.1002/ajmg.c.31755

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  • Hereditary spastic paraplegia masqueraded by congenital melanocytic nevus syndrome: Dual pathogenesis of germline non-mosaicism and somatic mosaicism. 査読 国際誌

    Yuri Sakaguchi, Tomoko Uehara, Marie Sasaki, Kimino Fujimura, Kazuo Kishi, Kenjiro Kosaki, Toshiki Takenouchi

    European journal of medical genetics   63 ( 4 )   103803 - 103803   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurocutaneous disorders are caused by germline and/or somatic mutations and involve the integument and central nervous systems. Congenital melanocytic nevus syndrome is characterized by melanotic skin lesions caused by somatic mutations at codon 61 in NRAS. A large cutaneous lesion raises the risk of central nervous system involvement. We report an 8-year-old girl with a congenital giant pigmented nevus that covered almost her entire back. Despite the absence of any radiological evidence of intracranial melanosis, the patient exhibited progressive limb spasticity with preserved intellectual ability. An extensive genetic analysis identified a specific class of heterozygous germline mutation in SPAST, p.(Arg499His), which is responsible for hereditary spastic paraplegia with infantile onset. In addition, a known heterozygous somatic mutation in NRAS, p.(Gln61Lys) was detected in the cutaneous lesion. This observation recapitulates concomitant mosaicism and non-mosaicism within a single individual and suggests that the possibility of a dual genetic diagnosis should be considered when neurological decline is observed in a patient with a neurocutaneous disorder without any detectable intracranial lesions.

    DOI: 10.1016/j.ejmg.2019.103803

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  • A case of autism spectrum disorder with cleft lip and palate carrying a mutation in exon 8 of AUTS2. 査読 国際誌

    Saki Saeki, Takashi Enokizono, Kazuo Imagawa, Hiroko Fukushima, Daigo Kajikawa, Aiko Sakai, Mai Tanaka, Tatsuyuki Ohto, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Kosaki Kenjiro, Hidetoshi Takada

    Clinical case reports   7 ( 11 )   2059 - 2063   2019年11月

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    記述言語:英語  

    We report a patient with autism and cleft lip and palate carrying a de novo heterozygous AUTS2 mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome.

    DOI: 10.1002/ccr3.2377

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  • De novo NSF mutations cause early infantile epileptic encephalopathy. 査読 国際誌

    Hisato Suzuki, Takeshi Yoshida, Naoya Morisada, Tomoko Uehara, Kenjiro Kosaki, Katsunori Sato, Kohei Matsubara, Toshiyuki Takano-Shimizu, Toshiki Takenouchi

    Annals of clinical and translational neurology   6 ( 11 )   2334 - 2339   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy.

    DOI: 10.1002/acn3.50917

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  • CNOT2 haploinsufficiency causes a neurodevelopmental disorder with characteristic facial features. 査読 国際誌

    Uehara T, Tsuchihashi T, Yamada M, Suzuki H, Takenouchi T, Kosaki K

    American journal of medical genetics. Part A   179 ( 12 )   2506 - 2509   2019年9月

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    記述言語:英語  

    DOI: 10.1002/ajmg.a.61356

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  • Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers. 査読 国際誌

    Suzuki H, Takenouchi T, Uehara T, Takasago S, Ihara S, Yoshihashi H, Kosaki K.

    American Journal of Medical Genetics A.   179 ( 8 )   1628 - 1630   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.

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  • Noninvasive diagnosis of TRIT1-related mitochondrial disorder by measuring i6 A37 and ms2 i6 A37 modifications in tRNAs from blood and urine samples. 査読 国際誌

    Takenouchi T, Wei FY, Suzuki H, Uehara T, Takahashi T, Okazaki Y, Kosaki K, Tomizawa K

    American journal of medical genetics. Part A   179 ( 8 )   1609 - 1614   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.61211

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  • SATB2-associated syndrome in patients from Japan: Linguistic profiles. 査読 国際誌

    Yamada M, Uehara T, Suzuki H, Takenouchi T, Yoshihashi H, Suzumura H, Mizuno S, Kosaki K.

    American Journal of Medical Genetics A.   179 ( 6 )   896 - 899   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cleft palate can be classified as either syndromic or nonsyndromic. SATB2-associated syndrome is one example of a syndromic cleft palate that is accompanied by intellectual disability, and various dental anomalies. SATB2-associated syndrome can be caused by several different molecular mechanisms including intragenic mutations and deletions of SATB2. Here, we report two patients with SATB2 truncating mutations (p.Arg239* and p.Asp702Thrfs*38) and one with a 4.4 megabase deletion including the SATB2 locus. All three patients had cleft palate and other dysmorphic features including macrodontia wide diastema. None of the three patients had acquired any meaningful words at the age of 5 years. In a review of the linguistic natural history of presently reported three patients and 30 previously reported patients, only two patients had attained verbal skills beyond speaking a few words. This degree of delayed speech contrasts with that observed in the prototypic form of syndromic cleft palate, 22q11.2 deletion syndrome. The recognition of SATB2-associated syndrome prior to palatoplasty would be important for plastic surgeons and the families of patients because precise diagnosis should provide predictive information regarding the future linguistic and intellectual abilities of the patients. Macrodontia with a wide diastema and cleft palate is a helpful and highly suggestive sign for the diagnosis of SATB2-associated syndrome.

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  • Clinical Aspects and Genetic Analysis of Pediatric Neurofibromatosis Type 1 with Neurological Complications(和訳中) 査読

    Fujita Kenji, Yamashita Kanako, Hoshina Takao, Hikita Norikatsu, Shimono Taro, Fukai Kazuyoshi, Takenouchi Toshiki, Uehara Tomoko, Kosaki Kenjiro, Saya Hideyuki, Hamazaki Takashi, Seto Toshiyuki

    大阪市医学会 Osaka City Medical Journal   65 ( 1 )   41 - 54   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • A novel missense PTEN mutation identified in a patient with macrocephaly and developmental delay. 国際誌

    Ueno Y, Enokizono T, Fukushima H, Ohto T, Imagawa K, Tanaka M, Sakai A, Suzuki H, Uehara T, Takenouchi T, Kosaki K, Takada H

    Hum Genome Var.   6   25 - 25   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41439-019-0056-8.

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  • CNOT2 as the critical gene for phenotypes of 12q15 microdeletion syndrome 国際誌

    Uehara T, Takenouchi T, Yamaguchi Y, Daimon Y, Suzuki H, Sakaguchi Y, Kosaki K

    American Journal of Medical Genetics, Part A   179 ( 4 )   659 - 662   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Journal of Medical Genetics, Part A  

    © 2019 Wiley Periodicals, Inc. Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)-negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4-NOT complex. Disruption of the CCR4-NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12-year-old female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly.

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  • Schuurs-Hoeijmakers syndrome in two patients from Japan. 査読 国際誌

    Hoshino Y, Enokizono T, Imagawa K, Tanaka R, Suzuki H, Fukushima H, Arai J, Sumazaki R, Uehara T, Takenouchi T, Kosaki K

    American journal of medical genetics. Part A   179 ( 3 )   341 - 343   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Schuurs-Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date,<br />
    28 patients with a recurrent de novo PACS1 mutation (c.607C &gt; T) have been reported, primarily<br />
    in Western populations. Here, we describe two Japanese patients with Schuurs-Hoeijmakers<br />
    syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each<br />
    patient presented novel clinical phenotypes. One patient presented with involuntary movements<br />
    and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1<br />
    mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms<br />
    along with the neurodevelopmental processes. The second patient was diagnosed with<br />
    lipomyelomeningocele during an examination for severe constipation at the age of 2 years and<br />
    8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of<br />
    cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis<br />
    of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients<br />
    with Schuurs-Hoeijmakers syndrome was not fully recognized, additional studies are needed to<br />
    clarify the clinical spectrum.

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  • Pathogenetic basis of Takenouchi-Kosaki syndrome: Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model. 査読 国際誌

    Uehara T, Suzuki H, Okamoto N, Kondoh T, Ahmad A, O'Connor BC, Yoshina S, Mitani S, Kosaki K, Takenouchi T

    Scientific reports   9 ( 1 )   4418 - 4418   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin 査読 国際誌

    Toshiki Takenouchi, Hiroyuki Shimada, Tomoko Uehara, Yae Kanai, Takao Takahashi, Kenjiro Kosaki

    EUROPEAN JOURNAL OF MEDICAL GENETICS   62 ( 2 )   93 - 95   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ejmg.2018.06.003

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  • Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution 国際誌

    Takenouchi T, Sakamoto Y, Sato H, Suzuki H, Uehara T, Ohsone Y, Kosaki K

    American Journal of Medical Genetics, Part A   176 ( 12 )   2777 - 2780   2018年12月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Journal of Medical Genetics, Part A  

    © 2018 Wiley Periodicals, Inc. The TWIST family is a group of highly conserved basic helix–loop–helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre–Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre–Chotzen syndrome and Sweeney–Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C&gt;G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney–Cox

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  • Expanding Phenotype of Nephronophthisis-Related Ciliopathy 査読 国際誌

    Kawaguchi Takahisa, Yoshida Tadashi, Hirahashi Junichi, Uehara Tomoko, Takenouchi Toshiki, Kosaki Kenjiro, Itoh Hiroshi, Hayashi Matsuhiko

    Nephron   140 ( 1 )   1 - 5   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    <p>Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G&gt;A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.</p>

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  • Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells. 国際誌

    Ritsuko Harigai, Shigeki Sakai, Hiroyuki Nobusue, Chikako Hirose, Oltea Sampetrean, Noriaki Minami, Yukie Hata, Takashi Kasama, Takanori Hirose, Toshiki Takenouchi, Kenjiro Kosaki, Kazuo Kishi, Hideyuki Saya, Yoshimi Arima

    Scientific reports   8 ( 1 )   6069 - 6069   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

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  • Growth pattern of Rahman syndrome. 査読 国際誌

    Toshiki Takenouchi, Tomoko Uehara, Kenjiro Kosaki, Seiji Mizuno

    American journal of medical genetics. Part A   176 ( 3 )   712 - 714   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, in a cohort study with "overgrowth syndrome with intellectual disability," five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This "lack of overgrowth in overgrowth syndrome" is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome.

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  • Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1. 査読 国際誌

    Toshiki Takenouchi, Mie Inaba, Tomoko Uehara, Takao Takahashi, Kenjiro Kosaki, Seiji Mizuno

    American journal of medical genetics. Part A   176 ( 2 )   431 - 437   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

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  • Three patients with DeSanto-Shinawi syndrome 査読 国際誌

    Uehara Tomoko, Ishige Takashi, Hattori Shigeto, Yoshihashi Hiroshi, Funato Michinori, Yamaguchi Yu, Takenouchi Toshiki, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   176 ( 6 )   1335 - 1340   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants 国際誌

    Uehara Tomoko, Takenouchi Toshiki, Kosaki Rika, Kurosawa Kenji, Mizuno Seiji, Kosaki Kenjiro

    European Journal of Medical Genetics   61 ( 5 )   243 - 247   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Respiratory arrest at the onset of idiopathic childhood occipital epilepsy of Gastaut 国際誌

    Keiko Funata, Tatsuhiko Shike, Toshiki Takenouchi, Yukio Yamashita, Takao Takahashi

    Brain and Development   40 ( 1 )   74 - 76   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    DOI: 10.1016/j.braindev.2017.06.009

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  • Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder. 査読 国際誌

    Sakaguchi A, Yamashita Y, Ishii T, Uehara T, Kosaki K, Takahashi T, Takenouchi T

    Eur J Med Genet.   62 ( 6 )   103537 - 103537   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ejmg.2018.09.004.

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  • Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis. 査読 国際誌

    Sakaguchi Y, Uehara T, Suzuki H, Sakamoto Y, Fujiwara M, Kosaki K, Takenouchi T

    Am J Med Genet A.   176 ( 11 )   2466 - 2469   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.40354.

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  • Body Temperature, Heart Rate, and Short-Term Outcome of Cooled Infants. 査読 国際誌

    Tsuda K, Iwata S, Mukai T, Shibasaki J, Takeuchi A, Ioroi T, Sano H, Yutaka N, Takahashi A, Takenouchi T, Osaga S, Tokuhisa T, Takashima S, Sobajima H, Tamura M, Hosono S, Nabetani M, Iwata O, Baby Cooling Registry of Japan Collaboration Team

    Ther Hypothermia Temp Manag.   9 ( 1 )   76 - 85   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1089/ther.2018.0019.

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  • Truncating mutation in CSNK2B and myoclonic epilepsy 国際誌

    Yuri Sakaguchi, Tomoko Uehara, Hisato Suzuki, Kenjiro Kosaki, Toshiki Takenouchi

    HUMAN MUTATION   38 ( 11 )   1611 - 1612   2017年11月

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  • Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A 査読

    Enokizono Takashi, Ohto Tatsuyuki, Tanaka Ryuta, Tanaka Mai, Suzuki Hisato, Sakai Aiko, Imagawa Kazuo, Fukushima Hiroko, Iwabuti Atsushi, Fukushima Takashi, Sumazaki Ryo, Uehara Tomoko, Takenouchi Toshiki, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   173 ( 10 )   2821 - 2825   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    <p>Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.</p>

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  • Abstract 3418: Additional Mutation in PTPN11 Gene Promotes Tumorigenesis of the NF1 Gene Mutated Cells

    Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya

    Cancer Research   77 ( 13_Supplement )   3418 - 3418   2017年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:American Association for Cancer Research (AACR)  

    Abstract

    The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) involved in negatively regulating the Ras signal by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. NF1 gene germline mutations cause Neurofibromatosis type 1 (NF1, von Recklinghausen disease). We hypothesized that additional genetic alterations promote the malignancy of NF1-associated tumors. To test our hypothesis, we inoculated a GFP-labeled human NF1-deficient cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and phosphorylation status of MEK and Akt than the parental sNF96.2-GFP cells. We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and our medical exome panel of 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants within coding regions of 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. We found a single base substitution (c.1508G&amp;gt;T, p.Gly503Val) in the PTPN11 gene, which encodes the tyrosine phosphatese SHP-2, and is associated with the regulation of the Ras signaling pathway. It is critical to note that constitutional gain-of-function mutations in the PTPN11 gene cause Noonan Syndrome in humans due to activation of the Ras pathway. To determine the role of PTPN11 mutation in NF1-associated tumors, we established a cell line overexpressing PTPN11mut in sNF96.2-GFP cells. We inoculated parental cells and PTPN11mut cells into the subcutaneous of nude mice, and we found that PTPN11mut cells show much higher tumorigenic activity than the parental sNF96.2-GFP cells. Our data suggests that this additional gene mutation in PTPN11 promotes the malignant characteristics of NF1-associated tumors.

    Citation Format: Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya. Additional mutation in PTPN11 gene promotes tumorigenesis of the NF1 gene mutated cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2017-3418

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  • Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene 国際誌

    Toshiki Takenouchi, Tomoru Miwa, Yoshiaki Sakamoto, Yuri Sakaguchi, Tomoko Uehara, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   173 ( 6 )   1631 - 1634   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.38126

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  • YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction 国際誌

    Michele Gabriele, Anneke T. Vulto-van Silfhout, Pierre-Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J. Pedurupillay, Petter Stromme, Jill A. Rosenfeld, Yunru Shao, William J. Craigen, Christian P. Schaaf, David Rodriguez-Buritica, Laura Farach, Jennifer Friedman, Perla Thulin, Scott D. McLean, Kimberly M. Nugent, Jenny Morton, Jillian Nicholl, Joris Andrieux, Asbjorg Stray-Pedersen, Pascal Chambon, Sophie Patrier, Sally A. Lynch, Susanne Kjaergaard, Pernille M. Torring, Charlotte Brasch-Andersen, Anne Ronan, Arie van Haeringen, Peter J. Anderson, Zoe Powis, Han G. Brunner, Rolph Pfundt, Janneke H. M. Schuurs-Hoeijmakers, Bregje W. M. van Bon, Stefan Lelieveld, Christian Gilissen, Willy M. Nillesen, Lisenka E. L. M. Vissers, Jozef Gecz, David A. Koolen, Giuseppe Testa, Bert B. A. de Vries

    AMERICAN JOURNAL OF HUMAN GENETICS   100 ( 6 )   907 - 925   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ajhg.2017.05.006

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  • Cover Image, Volume 173A, Number 5, May 2017

    Takenouchi Toshiki, Kuchikata Tomu, Yoshihashi Hiroshi, Fujiwara Mineko, Uehara Tomoko, Miyama Sahoko, Yamada Shiro, Kosaki Kenjiro

    American journal of medical genetics. Part A   173 ( 5 )   i   2017年5月

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    <p>The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype, DOI: 10.1002/ajmg.a.38167.</p>

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  • Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype 国際誌

    Toshiki Takenouchi, Tomu Kuchikata, Hiroshi Yoshihashi, Mineko Fujiwara, Tomoko Uehara, Sahoko Miyama, Shiro Yamada, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   173 ( 5 )   1353 - 1357   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Is that cranial deformity really due to sleeping position? 国際誌

    Hiroki Kajita, Yoshiaki Sakamoto, Toshiki Takenouchi, Tomoru Miwa, Takao Takahashi

    Pediatrics international : official journal of the Japan Pediatric Society   59 ( 4 )   494 - 496   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ped.13216

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  • Therapeutic hypothermia for neonatal encephalopathy 査読 国際誌

    Tsuda Kennosuke, Mukai Takeo, Iwata Sachiko, Shibasaki Jun, Tokuhisa Takuya, Ioroi Tomoaki, Sano Hiroyuki, Yutaka Nanae, Takahashi Akihito, Takeuchi Akihito, Takenouchi Toshiki, Araki Yuko, Sobajima Hisanori, Tamura Masanori, Hosono Shigeharu, Nabetani Makoto, Iwata Osuke

    Scientific Reports   7   39508 - 39508   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep39508

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  • Co-occurrence of Sturge-Weber syndrome and Klippel-Trenaunay-Weber syndrome phenotype 国際誌

    Sakaguchi Yuri, Takenouchi Toshiki, Uehara Tomoko, Kishi Kazuo, Takahashi Takao, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   173 ( 10 )   2831 - 2833   2017年

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  • A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak 査読 国際誌

    小崎 健次郎

    Hum Genome Var.   4   17033 - 17033   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Cover Image, Volume 170A, Number 12, December 2016

    Takenouchi Toshiki, Yoshihashi Hiroshi, Sakaguchi Yuri, Uehara Tomoko, Honda Masataka, Takahashi Takao, Kosaki Kenjiro, Miyama Sahoko

    American journal of medical genetics. Part A   170 ( 12 )   i   2016年12月

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    <p>The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation, DOI: 10.1002/ajmg.a.37861.</p>

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  • Hirschsprung Disease as a Yet Undescribed Phenotype in a Patient with ARID1B Mutation 国際誌

    Toshiki Takenouchi, Hiroshi Yoshihashi, Yuri Sakaguchi, Tomoko Uehara, Masataka Honda, Takao Takahashi, Kenjiro Kosaki, Sahoko Miyama

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   170 ( 12 )   3249 - 3252   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Jacobsen syndrome, Braddock–Carey syndrome, and Beyond 国際誌

    Takenouchi Toshiki, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   170 ( 10 )   2578 - 2579   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Homozygosity for Moyamoya Disease Risk Allele Leads to Moyamoya Disease with Extracranial Systemic and Pulmonary Vasculopathy 国際誌

    Hiroyuki Fukushima, Toshiki Takenouchi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   170 ( 9 )   2453 - 2456   2016年9月

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  • Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia 国際誌

    Toshiki Takenouchi, Nobuhiko Okamoto, Shinobu Ida, Tomoko Uehara, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   170 ( 4 )   852 - 855   2016年4月

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  • Childhood Sjögren syndrome presenting as acute brainstem encephalitis 国際誌

    Matsui Yoriko, Takenouchi Toshiki, Narabayashi Atsushi, Ohara Kentaro, Nakahara Tadaki, Takahashi Takao

    Brain and Development   38 ( 1 )   158 - 162   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability 国際誌

    Takenouchi Toshiki, Miura Kiyokuni, Uehara Tomoko, Mizuno Seiji, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   170 ( 10 )   2587 - 2590   2016年

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  • Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay 国際誌

    Toshiki Takenouchi, Rika Kosaki, Takahiro Niizuma, Kenichiro Hata, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   167 ( 11 )   2822 - 2825   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.37275

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  • Adult phenotype of Russell-Silver syndrome: A molecular support for Barker-Brenner's theory 国際誌

    Toshiki Takenouchi, Midori Awazu, Thomas Eggermann, Kenjiro Kosaki

    CONGENITAL ANOMALIES   55 ( 3 )   167 - 169   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia 国際誌

    Toshiki Takenouchi, Yuki Sugiura, Takayuki Morikawa, Tsuyoshi Nakanishi, Yoshiko Nagahata, Tadao Sugioka, Kurara Honda, Akiko Kubo, Takako Hishiki, Tomomi Matsuura, Takao Hoshino, Takao Takahashi, Makoto Suematsu, Mayumi Kajimura

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM   35 ( 5 )   794 - 805   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/jcbfm.2014.253

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  • Mosaic Overgrowth with Fibroadipose Hyperplasia Due to AKT1 Mutation 国際誌

    Toshiki Takenouchi, Yoshiaki Sakamoto, Chiharu Torii, Kenichiro Hata, Rika Kosaki, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   167 ( 4 )   907 - 909   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 次世代シークエンサーと解析パネルを用いたNF1遺伝子診断法の構築 査読

    丸岡 亮, 武内 俊樹, 清水 厚志, 鳥居 千春, 三須 久美子, 日笠 幸一郎, 松田 文彦, 太田 有史, 谷戸 克己, 倉持 朗, 有馬 好美, 大塚 藤男, 吉田 雄一, 森山 啓司, 小崎 里華, 新村 眞人, 佐谷 秀行, 小崎 健次郎

    日本レックリングハウゼン病学会雑誌   6 ( 1 )   79 - 79   2015年4月

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    記述言語:日本語   出版者・発行元:日本レックリングハウゼン病学会  

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  • Paramagnetic Signals in the Globus Pallidus as Late Radiographic Sign of Juvenile-Onset GM1 Gangliosidosis 国際誌

    Toshiki Takenouchi, Rika Kosaki, Kazuhiko Nakabayashi, Kenichiro Hata, Takao Takahashi, Kenjiro Kosaki

    PEDIATRIC NEUROLOGY   52 ( 2 )   226 - 229   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2014.09.022

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  • Novel Overgrowth Syndrome Phenotype Due to Recurrent De Novo PDGFRB Mutation 国際誌

    Toshiki Takenouchi, Yu Yamaguchi, Akiko Tanikawa, Rika Kosaki, Hideyuki Okano, Kenjiro Kosaki

    JOURNAL OF PEDIATRICS   166 ( 2 )   483 - 486   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jpeds.2014.10.015

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  • Porencephaly in a Fetus and HANAC in Her Father: Variable Expression of COL4A1 Mutation 国際誌

    Toshiki Takenouchi, Masaki Ohyagi, Chiharu Torii, Rika Kosaki, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   167 ( 1 )   156 - 158   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36823

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  • The Baby Cooling Project of Japan to Implement Evidence-Based Neonatal Cooling 国際誌

    Osuke Iwata, Toshiki Takenouchi, Sachiko Iwata, Makoto Nabetani, Takeo Mukai, Jun Shibasaki, Kennosuke Tsuda, Takuya Tokuhisa, Hisanori Sobajima, Masanori Tamura

    THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT   4 ( 4 )   173 - 179   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1089/ther.2014.0015

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  • The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study.

    Maruoka R, Takenouchi T, Torii C, Shimizu A, Misu K, Higasa K, Matsuda F, Ota A, Tanito K, Kuramochi A, Arima Y, Otsuka F, Yoshida Y, Moriyama K, Niimura M, Saya H, Kosaki K

    Genet Test Mol Biomarkers   18 ( 11 )   722 - 735   2014年11月

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    記述言語:英語  

    We assessed the validity of a next-generation sequencing protocol using in-solution hybridization-based enrichment to identify NF1 mutations for the diagnosis of 86 patients with a prototypic genetic syndrome, neurofibromatosis type 1. In addition, other causative genes for classic genetic syndromes were set as the target genes for coverage analysis.<br />
    The protocol identified 30 nonsense, 19 frameshift, and 8 splice-site mutations, together with 10 nucleotide substitutions that were previously reported to be pathogenic. In the remaining 19 samples, 10 had single-exon or multiple-exon deletions detected by a multiplex ligation-dependent probe amplification method and 3 had missense mutations that were not observed in the normal Japanese SNP database and were predicted to be pathogenic. Coverage analysis of the genes other than the NF1 gene included on the same diagnostic panel indicated that the mean coverage was 115-fold, a sufficient depth for mutation detection.<br />
    The overall mutation detection rate using the currently reported method in 86 patients who met the clinical diagnostic criteria was 92.1% (70/76) when 10 patients with large deletions were excluded. The results validate the

    DOI: 10.1089/gtmb.2014.0109

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  • The Use of Next-Generation Sequencing in Molecular Diagnosis of Neurofibromatosis Type 1: A Validation Study 国際誌

    Ryo Maruoka, Toshiki Takenouchi, Chiharu Torii, Atsushi Shimizu, Kumiko Misu, Koichiro Higasa, Fumihiko Matsuda, Arihito Ota, Katsumi Tanito, Akira Kuramochi, Yoshimi Arima, Fujio Otsuka, Yuichi Yoshida, Keiji Moriyama, Michihito Niimura, Hideyuki Saya, Kenjiro Kosaki

    GENETIC TESTING AND MOLECULAR BIOMARKERS   18 ( 11 )   722 - 735   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1089/gtmb.2014.0109

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  • Severe Craniosynostosis With Noonan Syndrome Phenotype Associated With SHOC2 Mutation: Clinical Evidence of Crosslink Between FGFR and RAS Signaling Pathways 国際誌

    Toshiki Takenouchi, Yoshiaki Sakamoto, Tomoru Miwa, Chiharu Torii, Rika Kosaki, Kazuo Kishi, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   164 ( 11 )   2869 - 2872   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36705

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  • Four-Decade-Old Mummified Umbilical Tissue Making Retrospective Molecular Diagnosis of Ornithine Carbamoyltransferase Deficiency 国際誌

    Toshiki Takenouchi, Yuki Tsukahara, Reiko Horikawa, Kenjiro Kosaki, Rika Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   164 ( 10 )   2679 - 2681   2014年10月

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  • Cilostazol strengthens the endothelial barrier of postcapillary venules from the rat mesentery in situ 国際誌

    Yasoo Sugiura, Takayuki Morikawa, Toshiki Takenouchi, Makoto Suematsu, Mayumi Kajimura

    PHLEBOLOGY   29 ( 9 )   594 - 599   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1177/0268355513497361

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  • A Pediatric Case of Antibiotic-Associated Hemorrhagic Colitis Caused by Klebsiella Oxytoca. 査読 国際誌

    Yamada M, Yamazawa K, Sekiguchi S, Shinjoh M, Tomita K, Takenouchi T, Takahashi T

    Glob Pediatr Health   1   2333794X14550525   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1177/2333794X14550525

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  • Multiple cerebral aneurysms after myxomatous stroke 国際誌

    Toshiki Takenouchi, Ayumi Sasaki, Takao Takahashi

    ARCHIVES OF DISEASE IN CHILDHOOD   99 ( 9 )   849 - 849   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1136/archdischild-2013-305807

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  • Progressive cognitive decline in an adult patient with cleidocranial dysplasia 国際誌

    Toshiki Takenouchi, Wakiro Sato, Chiharu Torii, Kenjiro Kosaki

    EUROPEAN JOURNAL OF MEDICAL GENETICS   57 ( 7 )   319 - 321   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ejmg.2014.04.015

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  • SOX9 dimerization domain mutation mimicking type 2 collagen disorder phenotype 国際誌

    Toshiki Takenouchi, Yohei Matsuzaki, Kazuka Yamamoto, Keisuke Kosaki, Chiharu Torii, Takao Takahashi, Kenjiro Kosaki

    EUROPEAN JOURNAL OF MEDICAL GENETICS   57 ( 6 )   298 - 301   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ejmg.2014.03.012

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  • Somatic CTNNB1 Mutation in Hepatoblastoma from a Patient with Simpson- Golabi- Behmel Syndrome and Germline GPC3 Mutation 国際誌

    Rika Kosaki, Toshiki Takenouchi, Noriko Takeda, Masayo Kagami, Kazuhiko Nakabayashi, Kenichiro Hata, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   164 ( 4 )   993 - 997   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36364

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  • Multiple café au lait spots in familial patients with MAP2K2 mutation 国際誌

    Takenouchi Toshiki, Shimizu Atsushi, Torii Chiharu, Kosaki Rika, Takahashi Takao, Saya Hideyuki, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A   164 ( 2 )   392 - 396   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36288

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  • 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay 国際誌

    Toshiki Takenouchi, Noriko Hashida, Chiharu Torii, Rika Kosaki, Takao Takahashi, Kenjiro Kosaki

    American Journal of Medical Genetics, Part A   164 ( 2 )   456 - 460   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36240

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  • Severe Congenital Lipodystrophy and a Progeroid Appearance: Mutation in the Penultimate Exon of FBN1 Causing a Recognizable Phenotype 国際誌

    Toshiki Takenouchi, Mariko Hida, Yoshiaki Sakamoto, Chiharu Torii, Rika Kosaki, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   161 ( 12 )   3057 - 3062   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.36157

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  • Daytime somnolence in an adult with smith-magenis syndrome 国際誌

    Toshiki Takenouchi, Hideyuki Saito, Naoki Oishi, Hiroyuki Fukushima, Rika Kosaki, Chiharu Torii, Takao Takahashi, Kosaki Kenjiro

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   161A ( 7 )   1803 - 1805   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35936

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  • Severe obstructive sleep apnea in loeys-dietz syndrome successfully treated using continuous positive airway pressure 国際誌

    Toshiki Takenouchi, Hideyuki Saito, Ryo Maruoka, Naoki Oishi, Chiharu Torii, Jun Maeda, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   161A ( 7 )   1733 - 1736   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35953

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  • Persistent Hypertension Despite Successful Dilation of a Stenotic Renal Artery in a Boy With Neurofibromatosis Type 1 国際誌

    Keisuke Ueda, Midori Awazu, Yoriko Konishi, Toshiki Takenouchi, Sachiko Shimozato, Kenjiro Kosaki, Takao Takahashi

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   161A ( 5 )   1154 - 1157   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35829

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  • Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis 国際誌

    Toshiki Takenouchi, Sachiko Nishina, Rika Kosaki, Chiharu Torii, Ritsuko Furukawa, Takao Takahashi, Kenjiro Kosaki

    EUROPEAN JOURNAL OF MEDICAL GENETICS   56 ( 1 )   50 - 53   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ejmg.2012.10.007

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  • Catastrophic autonomic crisis with cardiovascular collapse in spinal muscular atrophy with respiratory distress type 1 国際誌

    Toshihiro Nomura, Toshiki Takenouchi, Hiroyuki Fukushima, Sachiko Shimozato, Kenjiro Kosaki, Takao Takahashi

    Journal of Child Neurology   28 ( 7 )   949 - 951   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE Publications Inc.  

    DOI: 10.1177/0883073812453321

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  • Gas biology: Tiny molecules controlling metabolic systems

    Mayumi Kajimura, Tsuyoshi Nakanishi, Toshiki Takenouchi, Takayuki Morikawa, Takako Hishiki, Yoshinori Yukutake, Makoto Suematsu

    RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY   184 ( 2 )   139 - 148   2012年11月

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  • 12q14 Microdeletion Syndrome and Short Stature With or Without Relative Macrocephaly 国際誌

    Toshiki Takenouchi, Keisuke Enomoto, Toshihiko Nishida, Chiharu Torii, Tadaharu Okazaki, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 10 )   2542 - 2544   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35527

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  • Microduplication of Xq24 and Hartsfield Syndrome With Holoprosencephaly, Ectrodactyly, and Clefting 国際誌

    Toshiki Takenouchi, Hironobu Okuno, Rika Kosaki, Daisuke Ariyasu, Chiharu Torii, Suketaka Momoshima, Naoki Harada, Hiroshi Yoshihashi, Takao Takahashi, Midori Awazu, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 10 )   2537 - 2541   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35465

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  • Tissue-Limited Ring Chromosome 18 Mosaicism as a Cause of Pitt-Hopkins Syndrome 国際誌

    Toshiki Takenouchi, Tatsuhiko Yagihashi, Hiroyuki Tsuchiya, Chiharu Torii, Kumiko Hayashi, Rika Kosaki, Shinji Saitoh, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 10 )   2621 - 2623   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35230

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  • Congenital corneal staphyloma as a complication of Kabuki syndrome 国際誌

    Ryuma Tanaka, Toshiki Takenouchi, Keiko Uchida, Takeshi Sato, Hiroyuki Fukushima, Hiroshi Yoshihashi, Takao Takahashi, Kazuo Tsubota, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 8 )   2000 - 2002   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35453

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  • Posterior cerebral artery dissection on a serial magnetic resonance angiography 国際誌

    Toshiki Takenouchi, Sachiko Shimozato, Hirokazu Fujiwara, Suketaka Momoshima, Takao Takahashi

    BRAIN & DEVELOPMENT   34 ( 5 )   396 - 399   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.braindev.2011.06.012

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  • Hypothermia for neonatal encephalopathy: Nationwide Survey of Clinical Practice in Japan as of August 2010 国際誌

    Osuke Iwata, Makoto Nabetani, Toshiki Takenouchi, Takayuki Iwaibara, Sachiko Iwata, Masanori Tamura

    ACTA PAEDIATRICA   101 ( 5 )   e197 - e202   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1651-2227.2011.02562.x

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  • Hydrocephalus With Hirschsprung Disease: Severe End of X-linked Hydrocephalus Spectrum 国際誌

    Toshiki Takenouchi, Mie Nakazawa, Yonehiro Kanemura, Sachiko Shimozato, Mami Yamasaki, Takao Takahashi, Kenjiro Kosaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 4 )   812 - 815   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.35245

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  • Therapeutic hypothermia for neonatal encephalopathy: JSPNM & MHLW Japan Working Group Practice Guidelines Consensus Statement from the Working Group on Therapeutic Hypothermia for Neonatal Encephalopathy, Ministry of Health, Labor and Welfare (MHLW), Japan, and Japan Society for Perinatal and Neonatal Medicine (JSPNM)

    Toshiki Takenouchi, Osuke Iwata, Makoto Nabetani, Masanori Tamura

    BRAIN & DEVELOPMENT   34 ( 2 )   165 - 170   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.braindev.2011.06.009

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  • Changing Pattern of Perinatal Brain Injury in Term Infants in Recent Years 国際誌

    Toshiki Takenouchi, Ericalyn Kasdorf, Murray Engel, Amos Grunebaum, Jeffrey M. Perlman

    PEDIATRIC NEUROLOGY   46 ( 2 )   106 - 110   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2011.11.011

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  • Past, present and future of hypothermic neuroprotection for neonatal encephalopathy in Japan: Time to say good-by to the old remedies 国際誌

    Osuke Iwata, Toshiki Takenouchi

    BRAIN & DEVELOPMENT   34 ( 2 )   163 - 164   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.braindev.2011.06.008

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  • Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway 国際誌

    Takayuki Morikawa, Mayumi Kajimura, Tomomi Nakamura, Takako Hishiki, Tsuyoshi Nakanishi, Yoshinori Yukutake, Yoshiko Nagahata, Mami Ishikawa, Katsuji Hattori, Toshiki Takenouchi, Takao Takahashi, Isao Ishii, Kazuko Matsubara, Yasuaki Kabe, Shinichiro Uchiyama, Eiichiro Nagata, Moataz M. Gadalla, Solomon H. Snyder, Makoto Suematsu

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 4 )   1293 - 1298   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1073/pnas.1119658109

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  • Intraventricular Hemorrhage and White Matter Injury in the Preterm Infant

    Toshiki Takenouchi, Jeffrey M. Perlman

    Neurology   27 - 45   2012年

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Elsevier Inc.  

    DOI: 10.1016/B978-1-4377-3611-3.00003-1

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  • Delayed Onset of Sleep-Wake Cycling with Favorable Outcome in Hypothermic-Treated Neonates with Encephalopathy 国際誌

    Toshiki Takenouchi, Elayna O. Rubens, Vivien L. Yap, Gail Ross, Murray Engel, Jeffrey M. Perlman

    JOURNAL OF PEDIATRICS   159 ( 2 )   232 - 237   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jpeds.2011.01.006

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  • Reversible Diffuse White Matter Lesion in Alagille Syndrome 国際誌

    Toshiki Takenouchi, Sachiko Shimozato, Kenjiro Kosaki, Suketaka Momoshima, Takao Takahashi

    PEDIATRIC NEUROLOGY   45 ( 1 )   54 - 56   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2011.02.009

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  • Solitary Fibrous Tumor with Multiple Intracranial and Spinal Lesions: Case Report 国際誌

    Toshiki Takenouchi, Susan C. Pannullo, Philip E. Stieg, Ehud Lavi

    NEUROSURGERY   68 ( 4 )   E1148 - E1151   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1227/NEU.0b013e31820a1573

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  • Chain of Brain Preservation-A concept to facilitate early identification and initiation of hypothermia to infants at high risk for brain injury 国際誌

    Toshiki Takenouchi, Mathew Cuaycong, Gail Ross, Murray Engel, Jeffrey M. Perlman

    RESUSCITATION   81 ( 12 )   1637 - 1641   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.resuscitation.2010.08.001

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  • Germinal Matrix Hemorrhage in Zellweger Syndrome 国際誌

    Toshiki Takenouchi, G. Praveen Raju

    JOURNAL OF CHILD NEUROLOGY   25 ( 11 )   1398 - 1400   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1177/0883073810365545

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  • Restricted Diffusion in the Corpus Callosum in Hypoxic-Ischemic Encephalopathy 国際誌

    Toshiki Takenouchi, Linda A. Heier, Murray Engel, Jeffrey M. Perlman

    PEDIATRIC NEUROLOGY   43 ( 3 )   190 - 196   2010年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2010.04.014

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  • Alien Hand Syndrome in Parry-Romberg Syndrome 国際誌

    Toshiki Takenouchi, Gail E. Solomon

    PEDIATRIC NEUROLOGY   42 ( 4 )   280 - 282   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2009.11.010

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  • Stimulus-induced seizure in sick neonates-Novel observations with potential clinical implications 国際誌

    Toshiki Takenouchi, Vivien L. Yap, Murray Engel, Jeffrey M. Perlman

    EPILEPSIA   51 ( 2 )   308 - 311   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1528-1167.2009.02288.x

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  • Seizures Are Common in Term Infants Undergoing Head Cooling 国際誌

    Vivien Yap, Murray Engel, Toshiki Takenouchi, Jeffrey M. Perlman

    PEDIATRIC NEUROLOGY   41 ( 5 )   327 - 331   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.pediatrneurol.2009.05.004

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▼全件表示

書籍等出版物

  • 小児科診療(87巻5号)「それってほんとにITP?」

    ( 担当: 分担執筆 ,  範囲: ITPと鑑別すべき血液・免疫疾患 CDC42異常症,武内・小崎症候群)

    診断と治療社  2024年5月 

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  • 日本皮膚科学会雑誌(133巻13号)新・皮膚科セミナリウム 体細胞変異の関わる皮膚疾患 母斑症,皮膚癌から遺伝性疾患まで

    武内俊樹( 担当: 分担執筆 ,  範囲: 体細胞変異の視点から理解する母斑症(神経皮膚症候群)の病態と治療)

    日本皮膚科学会  2023年12月 

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  • 小児科(64巻10号)「日常診療で見落としたくない神経疾患」

    武内俊樹( 担当: 分担執筆 ,  範囲: 新たな診断・治療が可能となった疾患 神経線維腫症1型)

    金原出版  2023年10月 

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  • 小児科診療(87巻11号)遺伝学的検査 Up to Date

    武内俊樹( 担当: 共著 ,  範囲: 最先端プロジェクト その2 "Priority-i"を知ろう!)

    診断と治療社  2024年11月 

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  • 週刊医学のあゆみ(特集282巻5号)「小児医療の最先端」

    武内俊樹( 担当: 分担執筆 ,  範囲: 新生児集中治療における精緻・迅速なゲノム診断)

    医歯薬出版株式会社  2022年7月 

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    総ページ数:256   担当ページ:385-390   記述言語:日本語 著書種別:教科書・概説・概論

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    その他リンク: https://www.ishiyaku.co.jp/search/details.aspx?bookcode=286760

  • 周産期医学(52巻5号)「知っておくべき周産期・新生児領域の遺伝学的検査を展望する」

    武内俊樹( 担当: 分担執筆 ,  範囲: 新生児における網羅的遺伝子解析の意義と国内外の動向)

    泰山堂書店  2022年5月 

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    担当ページ:664-668  

    これまでの新生児医療は, 緻密な呼吸栄養管理などを中心とするsupportive careが中心であった. ここ数年で, 遺伝子治療や核酸医薬品をはじめとする新生児期発症の遺伝性疾患に対して病態に基づいた疾患特異的治療法が保険収載され, 臨床で使用されるようになった. 加えて, 人工知能やコンピュータ処理能力の著しい進歩により全ゲノム解析の期間が短縮された. これにより, 諸外国において重症新生児を対象とした網羅的遺伝子診断の臨床応用が広がりつつある. わが国においては, 小児期以降の未診断患者を対象とした網羅的遺伝子診断研究は行われてきたが, 重症新生児を対象とした迅速な網羅的遺伝子診断の取り組みはこれまでになかった. 筆者らは, 2019年から国内の周産期医療センターと連携し, 新生児集中治療室に入院する重症新生児に対する迅速な遺伝子診断の研究開発を行っている.

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  • 小児内科(54巻2号)「今知っておきたい ゲノム医療と遺伝子治療―基礎から臨床まで」

    武内俊樹( 担当: 分担執筆 ,  範囲: 重症新生児に対する迅速なゲノム診断の現状と展望)

    東京医学社  2022年2月 

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    担当ページ:357-360  

    「Key Points」
    (1)網羅的遺伝子解析に要する解析期間が短縮され, 欧米を中心に, ゲノム診断が小児・新生児集中治療の現場で活用され始めている.
    (2)わが国でも重症新生児に対するゲノム診断の研究が行われ, 約半数で診断が確定し, そのうち約半数で診療方針に影響があった.
    (3)重症新生児で迅速なゲノム診断が必要と考えられる場合には, 施設長の実施許可があれば, 研究参加できる枠組みが用意されている.
    (4)重症新生児に対するゲノム診断が将来的に保険収載されることが期待される.

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  • Mainichi Medical Journal(18巻2号)「世界の医学誌から」

    武内俊樹( 担当: 分担執筆 ,  範囲: PIK3CAの体細胞変異が孤発性海綿状血管腫を引き起こす)

    毎日新聞出版株式会社  2022年 

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    担当ページ:51  

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  • 小児科診療(84巻11号)「小児遺伝子疾患事典」

    武内俊樹( 担当: 分担執筆 ,  範囲: CDC42(関連疾患:武内・小崎症候群),NPC1 ( Niemann-Pick病C型))

    診断と治療社  2021年10月 

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    担当ページ:1426-1427, 1551-1552  

    【CDC42(関連疾患:武内・小崎症候群)】
    「1. 名称・分類・遺伝子座」 CDC42の遺伝子座位は1p36であり, RHOAおよびRAC1とともにスーパーファミリーを形成する低分子量Gタンパク質(small GTPase)である. 「2. 遺伝子の発現・機能」 Gタンパク質は2つに大別され, 1つは, 単量体で機能する低分子量Gタンパク質(small GTPase)であり, もう1つは, α, β, γのサブユニットからなるヘテロ三量体Gタンパク質である. CDC42の属する前者の低分子量Gタンパク質は, GTP結合タンパクであり, 結合している2種類のグアニンヌクレオチド(GTPあるいはGDP)の立体構造の違いにより, エフェクターへの結合能が変化し, 下流のシグナル伝達を制御する.

    【NPC1 ( Niemann-Pick病C型)】
    「1. 名称・分類, 遺伝子座」 NPC1の遺伝子座位は18q11.2であり, NPC2の遺伝子座位は14q24.3である. 「2. 遺伝子の構造・産物・発見の経緯」 NPC1は, 24のエクソンからなる遺伝子である. NPC1タンパクは, 1,278個のアミノ酸からなる13回膜貫通型膜タンパクであり, N末端のNPC領域はコレステロール結合能をもつ. 「3. 遺伝子の発現・機能」 コレステロールは, 通常, 細胞膜にあるLDL受容体を介して細胞内へ取り込まれる. ライソゾーム内に取り込まれたコレステロールエステルは, 酸性リパーゼにより遊離コレステロールとなる.

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  • Mainichi Medical Journal(17巻3号)「世界の医学誌から」

    武内俊樹( 担当: 分担執筆 ,  範囲: 脳性麻痺患者におけるエクソーム解析の分子遺伝学的診断率)

    2021年 

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    担当ページ:86  

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  • 小児科診療(83巻8号)「小児科医の将来を考える」

    武内俊樹( 担当: 分担執筆 ,  範囲: なぜ研究が必要か?(Ⅳ.もっと研究をしよう!))

    診断と治療社  2020年7月 

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    担当ページ:1075-1081  

    Summary
    ●人類は, これまで医学研究を通じて, エビデンスを積み上げることで医療を発展させてきた.
    ●研究活動のルールと診療活動のルールの違いや研究倫理についての理解が重要である.
    ●小児科学の社会医学の側面に加えて, 分子生物学, 再生医学, データサイエンス等の進歩により, 小児科学の研究対象は広がっている.

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  • 週刊医学のあゆみ(273巻7号)「未診断疾患イニシアチブ(IRUD)の成果」

    武内俊樹( 担当: 分担執筆 ,  範囲: 武内・小崎症候群の発見とCDC42阻害薬による治療法開発)

    医歯薬出版株式会社  2020年5月 

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    総ページ数:70   担当ページ:589-594   記述言語:日本語 著書種別:学術書

    網羅的遺伝子解析技術の飛躍的な進歩により, 臨床所見のみからは診断が困難であった希少疾患の確定診断や, 新規疾患の発見・確立が可能となった. "武内・小崎症候群(OMIM #616737)" は, 日本医療研究開発機構(AMED)の難病克服プロジェクトのひとつであるIRUD(未診断疾患イニシアチブ)を通じて, わが国より提唱, 確立されたヒト疾患である. 本疾患は知的障害, 巨大血小板性血小板減少症, リンパ浮腫, 感音性難聴, 脳構造異常, 免疫不全と易感染性, 甲状腺機能低下などを呈し, CDC42遺伝子にヘテロ接合性のアミノ酸置換変異(p.Tyr64Cysなど)を有することを特徴とする. 関連学会を中心に診断基準が作成され, 2019年7月から厚生労働省小児慢性特定疾病に収載されている. 国内外で複数の本疾患患者が同定されているが, 本疾患に対する治療法はいまだ存在せず, 疾患特異的治療法の開発が強く望まれている. IRUDをさらに発展させたIRUD-Beyondの一環として, 武内・小崎症候群に対する特異的治療法をドラッグリポジショニングにより開発することをめざす "CDC42阻害剤による武内・小崎症候群の治療法の開発研究班" が組織され, 活動を開始した. 細胞などを用いたin vitro実験系と疾患モデル動物などのin vivo系を組み合わせた研究により, 既承認薬のドラッグリポジショニングを効率的に推進し, 非臨床POC(proof of concept)を獲得することを目標としている.

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  • 周産期医学(50巻4号)「必携 専攻医と指導医のための新生児診療到達目標」

    田口寛子, 武内俊樹( 担当: 共著 ,  範囲: 新生児発作)

    泰山堂書店  2020年4月 

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    担当ページ:654-656  

    新生児期の痙攣性発作(seizure)は, 乳幼児期のそれとは大きく異なり, 明らかな身体症状を伴わず脳波上でのみ痙攣が確認されるなど, 見た目からだけでは非痙攣性の発作や動作と鑑別が困難な場面にしばしば遭遇する. 新生児痙攣は, 急性の脳障害, 神経疾患の徴候であることが多く, 注意を要する. 痙攣の診断が遅れたり, コントロールが不良な場合は, 神経学的予後に悪影響を及ぼすことがあるので, 非痙攣性発作と痙攣性発作を鑑別し, 必要な場合には迅速に治療を行う. 「新生児発作」 新生児の発作(spell)は, いわゆる真の痙攣である痙攣性発作(seizure)と非痙攣性発作に分類することができる.

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  • 小児内科(52巻8号)

    武内俊樹( 担当: 分担執筆 ,  範囲: 重症新生児に対する網羅的遺伝子解析の国内外の動向)

    東京医学社  2020年 

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    担当ページ:1123-1127  

    「重症の小児・新生児に対する網羅的遺伝子診断の課題と海外における検討」ヒトゲノム全塩基配列の解析を目指して1990年に始まったヒトゲノム計画は, サンガー法を用いて13年の歳月と30億ドル以上の資金を費やして行われた. 30年経った現在, 全ゲノム解析技術は加速度的に発展し, わずか数日間, 1000ドル程度の費用で全ゲノム解析が行えるようになった. 同時に, 遺伝子の分子機構の解明研究も飛躍的に進展し, 集中治療室への入室を要するような重症小児・新生児の診療に対する網羅的遺伝子解析の臨床応用が期待されている. ところが, 従来の網羅的遺伝子診断法は診断までに平均で半年以上の時間を要するため, 病状が時々刻々と変化する集中治療の医療現場で活用することは容易ではなかった. 2000年半ばに登場した次世代シーケンサーにより, 塩基配列の解読速度は大幅に短縮された.

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  • 健康障害をもつ小児の看護

    武内俊樹( 担当: 分担執筆 ,  範囲: 4章:系統臓器別疾患―Ⅸ神経・筋疾患)

    メヂカルフレンド社  2019年12月  ( ISBN:9784839233600

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    総ページ数:xxi, 631p   記述言語:日本語

    CiNii Books

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  • 指定難病ペディア2019(日本医師会生涯教育シリーズ)

    武内俊樹, 高橋孝雄( 担当: 共著 ,  範囲: 先天性大脳白質形成不全症(指定難病139))

    診断と治療社  2019年7月  ( ISBN:9784787824165

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    総ページ数:365   担当ページ:121   記述言語:日本語

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  • 遺伝子医学 29号(Vol.9 No.3)「未診断疾患イニシアチブ:使命・成果・展望」

    武内俊樹( 担当: 分担執筆 ,  範囲: CDC42 遺伝子異常症(武内・小崎症候群))

    株式会社メディカルドゥ  2019年7月  ( ISBN:9784909508027

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    担当ページ:52-57  

    武内・小崎症候群〔Takenouchi-Kosaki Syndrome(OMIM #616737)〕は,知的障害と巨大血小板性血小板減少症を特徴とし,CDC42 遺伝子の特定の新生突然変異に起因する稀な先天異常症候群である。本疾患は,日本医療研究開発機構(AMED)によって2015年から行われている「未診断疾患イニシアチブ(IRUD)」を通じて,似た症状を呈する複数の患者の研究協力により,新規ヒト疾患として発見・確立された。本疾患は,巨大血小板性血小板減少症,知的障害に加えて,脳構造異常,特徴的顔貌,感音性難聴,屈指,免疫不全による反復感染症,甲状腺機能低下症などの多彩な症状を呈することが特徴である。本疾患の病態については,まだ未解明な点が多く,今後の研究による病態解明が待たれるところである。血小板減少を伴う知的障害患者では,本疾患を鑑別に入れ,末梢血塗抹標本検査で,巨大血小板の有無を確認することが重要である。

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  • 小児科(2019年12月号)「新生児医療―最近の話題」

    武内俊樹( 担当: 分担執筆 ,  範囲: 新生児領域における網羅的遺伝子診断)

    金原出版  2019年3月 

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    担当ページ:1763-1771   記述言語:日本語

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  • 小児科(2018年11月増大号)「小児医療における診断・治療の進歩 2018」

    武内俊樹( 担当: 分担執筆 ,  範囲: 代表的な母斑症(神経皮膚症候群)−神経線維腫症1型、結節性硬化症、Noonan症候群、Sturge-Weber症候群、先天性巨大色素性母斑・神経皮膚黒色症)

    金原出版  2018年11月 

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    担当ページ:1725-1732   記述言語:日本語

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  • 小児内科(50巻1号)「小児医療・小児科医の将来と小児科医の役割」

    五十嵐隆, 阪下和美, 島袋林秀, 武内俊樹, 土畠智幸, 中林洋介, 西野多聞( 範囲: 雑誌『小児内科』創刊50周年記念 座談会)

    東京医学社  2018年1月 

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    担当ページ:5-18  

    -2017年10月25日 KKRホテル東京にて- <司会(五十嵐)> 雑誌『小児内科』は, このたび創刊50周年を迎えました. これを記念して, わが国の小児のおかれている現状と, 今後生じる小児の医療・保健の課題に対してどのような取り組みが必要かについて伺うために, 臨床・研究の現場で現在ご活躍中の中堅小児科医の先生方にお集まりいただきました. 小児科医のこれからの方向性についてご意見をいただければ幸いです. 「第1章 子どもたちのために」 ちょっとおせっかいかもしれないけれど -子育て支援と貧困について <司会> わが国は, すでに人口減少化の大きな流れのなかに入っています. 平成28年の合計特殊出生率は1.44, 出生数も98万人に減少し, 地方では過疎化が進んでいます. 子どもの育ちを総合的に評価するThe Child Development Indexで, わが国は世界一の地位を占めています.

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  • 小児科(2017年08月号)「日常診療で見逃されやすい頭部・神経疾患」

    前田直則, 松村和哉, 梅沢洸太郎, 坂口友理, 田村義輝, 若松太, 新庄正宜, 武内俊樹, 高橋孝雄( 担当: 共著 ,  範囲: 深鎮静により意識障害の診断が困難であったけいれん重積型急性脳症の1例)

    金原出版  2017年8月 

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    担当ページ:811-815  

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  • 小児科診療(80巻8号):症例報告

    白井陽子, 上原朋子, 武内俊樹, 呂彩子, 向井敏二, 小崎健次郎, 清水教一( 担当: 共著 ,  範囲: 網羅的遺伝子解析によりMowat-Wilson症候群と診断した14歳男子例)

    診断と治療社  2017年7月 

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    担当ページ:1003-1005  

    先天異常症候群では, 遺伝性または非遺伝性の多様な疾患が含まれ, 診断困難な場合が多い. 今回, 出生時に先天異常を認めたが診断がつかず, 14歳時に臨床的にCHARGE症候群と診断したものの, 次世代シーケンス法による網羅的遺伝子解析により Mowat-Wilson 症候群の確定診断となった14歳男子例を経験したので報告する. 「症例」症例 14歳, 男子. 主訴 発熱, 咳嗽. 家族歴 特記すべき事項なし. 出生歴・既往歴 妊娠38週6日, 2,890g, 自然分娩にて出生. 出生時に耳介低位, 耳介奇形, 停留精巣, 前置陰嚢, 尿道下裂, 口蓋垂裂を認めた. 染色体検査(G-分染法)は46,XYで異常を認めなかった. 腹部MRI検査にて腹腔内に精巣を認め, 前立腺は正常であった. 眼底検査および細隙灯顕微鏡検査では異常を認めなかった.

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  • ネオネイタルケア(春季増刊)

    武内俊樹( 担当: 分担執筆 ,  範囲: 新生児低酸素性虚血性脳症)

    メディカ出版  2017年 

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    担当ページ:128-133  

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  • 2015CoSTRに基づいた新生児低体温療法実践マニュアル

    武内俊樹( 担当: 分担執筆 ,  範囲: 1プロローグ 日本版ガイドライン骨子, 2適応基準と除外基準 01 新生児HIE の診断, 02 適応基準とは, 03 2015CoSTRに基づく適応基準, 3実践 07 導入:選択的頭部冷却の手順, 4知識 02 低体温療法を施行する施設の条件, 06 aEEGと標準脳波:基本編, 07 aEEGと標準脳波1:応用編, 10 現在の臨床エビデンスとガイドライン, 11 より効果的な低体温療法を求めて:今後の動向, 5実例 01 北米コーネル大学ニューヨークプレスビテリアン病院の場合, 付録 01 エントリー基準フローチャート.)

    東京医学社  2016年12月  ( ISBN:9784885632723

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    総ページ数:231p   記述言語:日本語

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  • 周産期医学(Vol.46 増刊号)「周産期医学必修知識 【新生児編】Part V 新生児 [生理, 発達, 適応と評価]」

    武内俊樹, 高橋孝雄( 担当: 共著 ,  範囲: 新生児の神経学的発達)

    東京医学社  2016年 

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    担当ページ:519-520  

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  • 周産期医学(Vol.46 増刊号)「周産期医学必修知識 【新生児編】 Part V 新生児 [疾患]」

    武内俊樹( 担当: 分担執筆 ,  範囲: 脳の形態異常)

    東京医学社  2016年 

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    担当ページ:708-709  

    脳の形態異常は, 顕微鏡的な形態異常から肉眼的な形態異常まで非常に多岐にわたる. 中枢神経系の中核をなす脳は, 神経幹細胞からの神経細胞の産生, 神経細胞の遊走, グリア細胞の形成, シナプス形成, ミエリン形成といった過程を経て形成される. このような脳の発生段階のいずれかに異常が生じた場合, その段階によってさまざまな形態異常を生じる. 脳の形態異常の原因には, 遺伝子異常などの内的要因だけでなく, 感染症や出血, 薬物曝露といった環境要因も含まれる. 以下に, 代表的な中枢神経系の形態異常について述べる. 「各論」 [1. 孔脳症 (porencephaly) ] 大脳半球に嚢疱または空洞がみられる脳形成異常であり, 脳性麻痺, 特に片麻痺の原因となる. このほかにも, てんかん, 精神運動発達遅滞を呈することがある. 胎生期における脳梗塞などの脳血管障害の結果として発生すると推測されているが, 多くの場合原因は不明である.

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  • 小児内科(47巻3号)「ピンポイント小児医療 特集 新生児医療の最前線〔新たに導入された医療〕」

    岩田欧介, 柴崎淳, 津田兼之介, 武内俊樹, 岩田幸子, 向井丈雄, 徳久琢也, 側島久典, 田村正徳, 細野茂春, 鍋谷まこと( 担当: 共著 ,  範囲: Baby Cooling Japan低体温療法施行症例登録が見据える脳保護療法の未来)

    東京医学社  2015年3月 

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    担当ページ:328-333  

    出生前後の低酸素や虚血によって中等度以上の脳症を発症した新生児にとって, 低体温療法は臨床エビデンスに支持される唯一の脳保護療法である. 一方で低体温療法の治療効果は, 6~9名を治療してようやく1名の予後を改善できるレベルにとどまる. 十分な効果を死守するために, 国内外の蘇生療法ガイドラインでは, 大規模ランダム化臨床研究(以下, 便宜上RCTと記載)で用いられた導入基準と方法を厳格に順守するように求めている. 本稿ではConsensus 2010による新生児低体温療法の推奨以降, 日本の新生児医療従事者が一丸となってエビデンスへの回帰を成し遂げた過程を簡単に振り返るとともに, 今後日本の臨床家がどのような戦略で低体温療法の効果を増大し, 世界へのエビデンス発信を進めるのかを, Baby cooling Japan登録症例の分析結果の考察を交えて議論する.

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  • 今日の治療指針(2015年版) : 私はこう治療している

    ( 担当: 分担執筆 ,  範囲: 22 新生児疾患:低酸素性虚血性脳症.)

    医学書院  2015年1月  ( ISBN:9784260020398

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    総ページ数:冊   記述言語:日本語

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  • 小児科(2014年7月号)「新生児期に特徴的なけいれん性疾患」

    武内俊樹( 担当: 分担執筆 ,  範囲: 低酸素性虚血性脳症・脳室内出血)

    金原出版  2014年7月 

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    担当ページ:1167-1173  

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  • NICUマニュアル

    武内俊樹( 担当: 分担執筆 ,  範囲: Ⅲ ハイリスク児Cリスクの予想される児への対応 新生児仮死蘇生後のケア, Eハイリスク児の病態・疾患別管理 新生児低酸素性虚血脳症.)

    金原出版  2014年7月  ( ISBN:9784307170680

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    総ページ数:xvi, 887p   記述言語:日本語

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  • Mainichi Medical Journal(10巻5号)「世界の医学誌から」

    武内俊樹( 担当: 分担執筆 ,  範囲: 13歳以下での近親者との死別は子の精神病発症リスクを高める)

    毎日新聞出版株式会社  2014年 

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    担当ページ:240-241  

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  • Mainichi Medical Journal(タブレット版)「世界の医学誌から」

    武内俊樹( 担当: 分担執筆 ,  範囲: 体外受精は出生の精神運動発達遅滞リスクを有意に上昇させる)

    毎日新聞出版株式会社  2013年12月 

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  • ネオネイタルケア(25巻9号)「実施方法と看護のポイントをやさしく学ぶ 赤ちゃんにやさしい低体温療法 まるわかりQ&A」

    武内俊樹, 小西順子( 担当: 共著 ,  範囲: (1)低体温療法の概要)

    メディカ出版  2012年9月 

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    担当ページ:906-909  

    「Q1 低酸素状態に陥った新生児の脳を冷やすことで, どのような脳保護メカニズムが働くのですか? 分かりやすく教えてください.」 低酸素性虚血性脳症とは, 胎盤血流の遮断を端緒として低酸素虚血に陥った神経細胞で有害な連鎖化学反応が起こり, 神経細胞が障害される現象である. 低体温療法は, 脳全体のエネルギー消費を抑え, これらの有害な化学反応を多段階で阻害することにより, 脳保護に働く. 「1. 低酸素性虚血に陥ると, 神経細胞はどのように障害されるか」低酸素性虚血性障害の強い神経細胞は壊死に陥る. 壊死を免れた神経細胞では, 再酸素化と再還流により, エネルギー代謝が一時的に回復する. しかし, 分子レベルでは有害な化学反応が進行しており, 一定の潜伏期間を経た後, 徐々にアポトーシス(神経細胞死)が起こり, 神経細胞が脱落する. 図1に示すように, 低酸素性虚血が起こると, ATP低下, 興奮性アミノ酸の放出, 低酸素性脱分極によるカルシウムイオンの細胞内流入など分子レベルの反応が次々と生じ, 最終的には一酸化窒素や活性酸素が産生される).

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  • Neurology:Neonatology Questions and Controversies

    Toshiki Takenouchi, Jeffrey M Perlman( 担当: 分担執筆 ,  範囲: Chapter 3 Intraventricular hemorrhage and white matter injury in preterm infant)

    Elsevier Saunders  2012年4月  ( ISBN:9781437736113

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    総ページ数:xiv, 350 p.   担当ページ:27-45   記述言語:英語

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  • Intraventricular hemorrhage and white matter injury in the preterm infant

    Takenouchi Toshiki, Perlman Jeffrey M

    2012年 

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    記述言語:英語

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  • 小児科(2011年11月増大号)「小児医療における診断・治療の進歩」

    武内俊樹( 担当: 分担執筆 ,  範囲: 新生児低酸素性虚血性脳症に対する低体温療法)

    金原出版  2011年11月 

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    担当ページ:1697-1702  

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  • JRC蘇生ガイドライン2010

    田村正徳, 和田雅樹, 石川源, 草川功, 五石圭司, 杉浦崇浩, 側島久典, 滝敦子, 武内俊樹, 中野怜二, 西田俊彦, 細野茂春, 正岡直樹, 森臨太郎.( 担当: 分担執筆 ,  範囲: 4章:新生児の蘇生(NCPR))

    へるす出版  2011年10月 

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    記述言語:日本語

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  • ネオネイタルケア(24巻 8号)「Q&Aで改訂点の根拠を知ろう 徹底理解!新しい新生児蘇生法」

    武内俊樹( 担当: 分担執筆 ,  範囲: Q12:蘇生後管理として低体温療法の実施が考慮されることが明記されましたが、Consensus 2010に加わったのはなぜでしょうか?適応基準, 推奨されている方法はありますか?あるいは施設のプロトコルに従ってもよいのでしょうか?)

    メディカ出版  2011年8月 

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    担当ページ:781-784  

    「これがエビデンスだ!」[現在のところ低体温療法だけが唯一, ヒトの新生児低酸素性虚血性脳症の予後を有意に改善することが科学的に証明されている治療法である. ] 欧米を中心に新生児低体温療法が広く行われるようになっているという世界的な流れを受けて, 新生児蘇生法の中でも標準治療として推奨された. 新生児低酸素性虚血性脳症は, 死亡または重篤な神経学的後遺症を残すことが多く, 最も重要な周産期疾患の一つである. 患児だけでなく, 家族そして社会全体の長期にわたる負担も大きな問題であり, 治療法が渇望されていた. しかしながら, 低酸素や虚血といった病態は根本的治療が難しく, これまで予後を改善させる治療法が存在しなかった. 近年, 動物実験から低体温療法の有効性が確認され, さらに複数の大規模臨床治験においてヒトでも比較的安全に有意に予後を改善することが示された. これを受けて, すでに欧米では低体温療法が広く行われるようになっている.

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  • 新生児・小児のための脳低温療法 : 日本脳低温療法学会公認テキスト

    武内俊樹( 担当: 分担執筆 ,  範囲: 5章脳低温療法の効果―2新生児:世界の現状.)

    メディカ出版  2011年7月  ( ISBN:9784840436922

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    総ページ数:150p   記述言語:日本語

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  • Consensus2010に基づく新生児低体温療法実践マニュアル

    武内俊樹( 担当: 分担執筆 ,  範囲: 3マニュアル基本編 1)現在の臨床エビデンスとガイドライン, 2)低体温療法を施行する施設の条件, 3) 低体温療法の適応基準と除外基準 基本編1-新生児HIEの診断の基本, 4)低体温療法の適応基準と除外基準 基本編2‐適応基準の基本的な考え方, 5)低体温療法の適応基準と除外基準 実践編-2010CoSTRに基づく適応基準, 6)aEEGと標準脳波 基本編, 7)aEEGと標準脳波 応用編-低体温療法の適応基準としてのaEEG, 10)低体温療法導入の実際-選択的頭部冷却の場合, 4マニュアル実例編 1)北米 コーネル大学ニューヨークプレスビテリアン病院の場合, 5まとめ 2)より効果的な低体温療法を求めて-今後の動向, 付録 1)日本版ガイドライン骨子, 2)エントリー標準フローチャート)

    東京医学社  2011年5月  ( ISBN:9784885632013

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    総ページ数:143p   記述言語:日本語

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  • 小児看護(34巻11号)「どこまでもやさしく!臨床に役立つ新生児の解剖・生理・生化学 神経系」

    有光威志, 武内俊樹, 池田一成( 担当: 共著 ,  範囲: 低体温療法の生理学・生化学:どのように新生児の脳を保護しているのか?)

    へるす出版  2011年 

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    担当ページ:1428-1433   記述言語:日本語

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  • 日本版救急蘇生ガイドライン2010に基づく新生児蘇生法テキスト(改訂第2版)

    武内俊樹( 担当: 分担執筆 ,  範囲: 5章その他の新しい推奨 Ⅱ蘇生後のケア 2低体温療法.)

    メジカルビュー社  2010年12月  ( ISBN:9784758310697

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    総ページ数:170   記述言語:日本語

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  • アレルギーの臨床(2010年12月臨時増刊号)「ヒスタミンH1受容体拮抗薬の臨床」

    高橋孝雄, 武内俊樹( 担当: 共著 ,  範囲: 小児科領域におけるヒスタミン受容体拮抗薬の使い方)

    北隆館  2010年12月 

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    担当ページ:1260-1264   記述言語:日本語 著書種別:学術書

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講演・口頭発表等

  • Genomic diagnosis in neonatal and pediatric acute care

    武内俊樹

    日本人類遺伝学会第69回大会:シンポジウム  2024年10月 

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  • 頭蓋縫合早期癒合症の分子機構と神経発達 招待

    武内俊樹

    第30回日本形成外科基礎学術集会:小児形成外科分野指導医認定委員会教育セミナー  2024年10月 

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  • ベッドサイドを起点とした小児難病・希少遺伝性疾患の基礎・臨床研究の展開 招待

    武内俊樹

    第56回日本小児呼吸器学会学術集会:教育講演  2024年9月 

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  • 新生児医療における迅速なゲノム診断の課題と展望

    武内俊樹

    第60回日本周産期・新生児医学会学術集会:シンポジウム  2024年7月 

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  • 新生児期の遺伝性疾患に対する迅速な診断と治療

    武内俊樹

    第127回日本小児科学会学術集会:シンポジウム  2024年4月 

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  • NF1の病態理解と分子標的薬による治療 招待

    武内俊樹

    第67回日本形成外科学会総会・学術集会:小児形成外科分野指導医教育セミナー  2024年4月 

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    会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

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  • Nationwide Acute Care Genomics for Sick Neonates and Infants in Japan 招待

    武内俊樹

    10th Anniversary Celebration of National Taiwan University Childrens Hospital and 3rd International Symposium  2024年3月30日 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 新生児・小児遺伝性疾患の網羅的ゲノム解析による診断と治療 招待

    武内俊樹

    札幌医科大学 臨床遺伝カンファレンス  2024年2月 

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  • Nationwide implementation of rapid genomic diagnostic network for sick newborn infants in Japan

    武内俊樹

    2023 American Society of Human Genetics annual meeting: Platform presentation  2023年11月 

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  • ヒトゲノム解析による疾患の確立と治療標的の探索 招待

    武内俊樹

    第4回理化学研究所DMP創薬セミナー  2023年9月 

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  • モデルマウスを用いた新規ヒト過成長症候群の頭蓋顎顔面先天異常の解析と治療戦略

    武内俊樹

    第63回日本先天異常学会学術集会:シンポジウム  2023年7月 

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  • 重症新生児に対する迅速なゲノム診断の現状と展望

    武内俊樹

    第59回日本周産期・新生児医学会学術集会:教育講演  2023年7月 

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    会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

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  • 網羅的遺伝子解析で得られるバリアントの解釈と家族への説明 招待

    武内俊樹

    第65回日本小児神経学会学術集会:実践教育セミナー9「エキスパートから学ぼう!遺伝学的検査結果の上手な伝え方」  2023年5月24日 

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  • 新生児集中治療室における精緻・迅速な遺伝子診断の現状と展望 招待

    武内俊樹

    第45回日本小児遺伝学会学術集会:教育講演  2023年1月28日 

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  • 重症新生児に対する迅速な遺伝子診断の臨床応用 招待

    武内俊樹

    日本脳神経外科学会第81回学術総会:シンポジウム  2022年9月30日 

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  • 頭蓋縫合早期癒合症の早期診断と遺伝学的背景 招待

    武内俊樹

    第18回craniosynostosis研究会  2022年6月20日 

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  • 体細胞変異の視点から理解する母斑症(神経皮膚症候群)の病態と治療 招待

    武内俊樹

    第121回日本皮膚科学会学術集会:教育講演  2022年6月5日 

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  • 新生児集中治療室における網羅的遺伝子解析の活用 招待

    武内俊樹

    第65回新生児成育医学会学術集会:教育セミナー  2021年5月8日 

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  • 新生児医療に革命をもたらすゲノム・シーケンシング 招待

    武内俊樹

    自由民主党政調調査会データヘルス推進特命委員会がんゲノム・AI等ワーキンググループ  2021年4月21日 

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  • Identification of Two New Disease Entities Through the Undiagnosed Disease Program at Our Institution 招待

    Toshiki Takenouchi

    3rd International Rare Diseases Research Consortium(Paris, France)  2017年2月9日 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 希少疾患と感覚器異常: 武内・小崎症候群の聴力障害 招待

    武内俊樹

    国立病院機構東京医療センター:第15回感覚器シンポジウム  2022年3月11日 

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  • ベッドサイドを起点とした網羅的アプローチによる新生児・小児神経疾患研究の展開 招待

    武内俊樹

    愛知県医療療育総合センター発達障害研究所公開セミナー  2021年12月10日 

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  • Research and Development on Precise and Rapid Genetic Diagnosis in Neonatal Intensive Care Unit 招待

    Toshiki Takenouchi

    International Neonatal Consortium Annual Meeting  2021年10月19日 

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  • “新しい治療”を創り出す:産学官の“現場”の若手たち 招待

    武内俊樹

    第29回日本耳科学会総会・学術講演会:ネクストジェネレーションセッション8  2019年10月12日 

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  • 新規疾患概念の確立と治療法開発についての今後の課題 招待

    武内俊樹

    日本人類遺伝学会第63回大会:シンポジウム「New syndromes, new concepts」  2018年10月12日 

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  • Learning while Teaching, Teaching while Learning 招待

    Toshiki Takenouchi

    第121回日本小児科学会学術集会:国際セッション4 JPS-KPS Joint Symposium  2018年4月22日 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 小児科におけるてんかん診療 招待

    武内俊樹

    慶應義塾大学医学部三四会第114回生涯教育セミナー  2018年2月10日 

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  • オミックスを用いた病態解明 招待

    武内俊樹

    第120回日本小児科学会学術集会:分野別シンポジウム5「新生児神経学」  2017年4月 

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    兼座長

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  • 血小板低下を伴う知的障害:武内・小崎症候群 招待

    武内俊樹

    第39回日本小児遺伝学会学術集会  2016年12月9日 

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  • 次世代遺伝子解析技術を用いた難病の遺伝子診断 招待

    武内俊樹

    第99回東京小児科医会学術講演会  2015年6月21日 

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  • 新生児脳低温療法の実際 招待

    武内俊樹

    第47回日本新生児周産期医学会学術集会:シンポジウム「新生児脳低温療法―日本において新生児脳低温療法は標準的医療となりうるか」  2011年7月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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▼全件表示

受賞

  • 日本小児科学会 学術研究賞

    2024年  

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  • 第6回日本医療研究開発大賞 日本医療研究開発機構(AMED)理事長賞

    2023年  

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    受賞国:日本国

    【受賞タイトル】
    「社会共創」の観点を重視した研究開発とゲノム解析による新生児・小児医療への貢献
    【功績】
    全国規模の拠点ネットワークを構築し、ゲノム解析による重症新生児への診断・治療に貢献する他、新規の先天異常症候群「武内・小崎症候群」を報告し、データシェアリングにより国内だけでなく海外の患児の確定診断に至った。

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  • 第20回小児医学川野賞

    2020年  

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  • 日本医師会医学研究奨励賞

    2016年  

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    受賞区分:出版社・新聞社・財団等の賞 

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  • 森永奉仕会研究奨励金特別賞太田敬三記念賞

    2013年  

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    受賞区分:出版社・新聞社・財団等の賞 

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  • 三四会奨励賞

    2015年  

    武内 俊樹

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    受賞国:日本国

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共同研究・競争的資金等の研究

  • 重症新生児に対する迅速なゲノム診断の医療実装に関する研究開発

    2024年04月 - 2027年03月

    日本医療研究開発機構(AMED)  成育疾患克服等総合研究事業-BIRTHDAY 

    【研究代表者】武内俊樹

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    担当区分:研究代表者 

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  • 新生児集中治療室における精緻・迅速な遺伝子診断に関する研究開発

    2019年04月 - 2024年03月

    日本医療研究開発機構(AMED)  成育疾患克服等総合研究事業-BIRTHDAY 

    【研究代表者】武内 俊樹

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    担当区分:研究代表者 

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  • CDC42阻害剤による武内・小崎症候群の治療法の開発

    2018年10月 - 2021年03月

    日本医療研究開発機構(AMED)  難治性疾患実用化研究事業 

    【研究代表者】武内 俊樹

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    担当区分:研究代表者 

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その他研究活動

  • 日本人類遺伝学会 臨床遺伝専門医・指導医

    2012年11月

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  • 日本小児神経学会 小児神経専門医

    2012年11月

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  • 日本小児科学会 小児科専門医・認定指導医

    2011年11月

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  • 米国小児科専門医 (American Board of Pediatrics, General Pediatrics)

    2009年10月

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  • 米国小児神経科専門医(American Board of Psychiatry and Neurology, Neurology with Special Qualification in Child Neurology)

    2009年09月

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担当授業科目

  • 小児医科学(発達神経病態学)実習 (2024年度) 特別  - その他

  • 小児医科学(発達神経病態学)演習 (2024年度) 特別  - その他

  • 小児医科学(発達神経病態学)I(演習・実習) (2024年度) 特別  - その他

  • 小児医科学(発達神経病態学)I(講義・演習) (2024年度) 特別  - その他

  • 小児医科学(発達神経病態学)II(演習・実習) (2024年度) 特別  - その他

  • 小児医科学(発達神経病態学)II(講義・演習) (2024年度) 特別  - その他

▼全件表示

 

社会貢献活動

  • AMED事業紹介動画「未診断疾患イニシアチブ(IRUD)」

    役割:出演, 取材協力

    国立研究開発法人日本医療研究開発機構(AMED)  2023年2月16日

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    対象: 高校生, 大学生, 大学院生, 教育関係者, 保護者, 研究者, 社会人・一般, 学術団体, 企業, 市民団体, 行政機関, メディア

    種別:インターネット

    臨床的な所見を有しながら通常の医療の中で診断に至ることが困難な患者さん(いわゆる未診断疾患患者)は、多数の医療機関で診断がつかず、原因もわからず、治療方法も見つからないまま、様々な症状に悩まされています。

    「未診断疾患イニシアチブ Initiative on Rare and Undiagnosed Diseases(IRUD) 」は、こうした未診断疾患患者さんの情報共有と診断確定、そして治療を見据えた病態解明やシーズ創出を目的として、平成27(2015)年から推進する研究開発プログラムで、AMEDが研究班と二人三脚で進めています。

    この動画では、IRUDの取組、最新の成果等についてご紹介しています。ぜひ、ご覧ください。

    0:22 IRUD概要:国立精神・神経医療研究センター 水澤 英洋 研究開発代表者
    1:48 IRUD Case1(既知の疾患):国立成育医療研究センター 松原 洋一 医師
    3:22 IRUD Case2(新しい疾患):慶應義塾大学医学部小児科学教室 武内 俊樹 医師
    5:11 IRUDの発展

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  • インタビュー「重症の赤ちゃんをゲノム解析で救う国家プロジェクト「Priority-i」とは?」

    役割:取材協力

    遺伝性疾患プラス  2022年10月24日

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    対象: 大学生, 大学院生, 保護者, 研究者, 社会人・一般, 学術団体, 企業, 市民団体, 行政機関, メディア

    種別:インターネット

    2022年2月、「重症で生まれて病気の原因が不明の赤ちゃん85人を対象にゲノム解析を行ったところ、約半数で原因が特定でき、さらにその約半数で、より適切な検査や治療方針に結び付いた」という内容のプレスリリースが慶應義塾大学から発表されました。遺伝性疾患プラスでも、この内容を広く読者にお伝えしたいと考え、ニュースとして公開したところ、多くの方々から反響を頂きました。この研究は、「新生児集中治療室における精緻・迅速な遺伝子診断に関する研究開発」、通称Priority-i(プライオリティ・アイ)と呼ばれ、遺伝性疾患が疑われる新生児・乳児(原則6か月以下)に対して迅速に遺伝子診断を行い、診療に役立てることを目的として実施されている国のプロジェクトです。当初は8都府県にある17の高度周産期医療センターとともに開始されましたが、現在は全国のより多くの医療機関へと規模を拡大して進められています。今回、Priority-iの研究代表者を務めておられる、慶應義塾大学医学部小児科学教室専任講師の武内俊樹先生に、より詳しい研究内容や将来展望などについて、お話を伺いました。

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メディア報道

  • 原因不明の重症赤ちゃん 遺伝子を解析、素早く治療 新聞・雑誌

    毎日新聞  2023年4月13日

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    原因不明の重い症状に苦しむ赤ちゃんの遺伝子を網羅的に調べて、迅速に診断や治療につなげるプロジェクトを慶応大などが進めている。これまでの取り組みでは半数近くの原因が判明、治療法が見つかったり、日常生活での注意点が分かったりした。2022年に拠点を全国に広げ、約80施設が参加している。

    【先端技術で判明率が向上/研究の拠点全国に広がる/家族を支援する体制必要】
    生まれてすぐに重い病気に苦しむ赤ちゃんは素早く病名を突き止めて治療を始める必要があるが、自分でどこが痛いかを説明できない。「Priority―i(プライオリティーアイ)」と題したプロジェクトの代表者である慶応大医学部小児科の武内俊樹専任講師は「見た目の症状や脳波、血液などで調べるのが一般的だが、症状がはっきりしない場合もあり、診断は難しかった」と話す。
    このプロジェクトは、生後半年ごろまでの赤ちゃんが対象。慶応大が、候補となる赤ちゃんを診療している施設からの相談を受け、年齢や症状から対象になると判断したら、遺伝の専門医やカウンセラーがプロジェクトの流れを親に説明。同意を得た後、赤ちゃんと親から採血して「次世代シーケンサー」という機器で遺伝子を解析する。(以下略)

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  • 赤ちゃん病因、ゲノムで特定 原因不明の半数で成功―慶大など インターネットメディア

    時事通信  2022年4月22日

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  • 原因不明の赤ちゃんの病気、ゲノム解析で半数解明 治療法の改善にも 新聞・雑誌

    朝日新聞デジタル  2022年2月4日

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    病気の原因がわからない赤ちゃんの全ての遺伝情報(ゲノム)を解析することで、全体の約半数で原因を特定できたとの研究結果を、慶応大を中心とする医療チームがまとめた。うち半数で検査や治療方針の変更につながり、ゲノム解析が重症新生児の診断や治療に役立ったという。
    研究には全国8都府県にある17の周産期母子医療センターなどが参加。2019年4月から21年3月までに新生児集中治療室(NICU)に入院し、原因がわからなかった85人の重症の赤ちゃんについて、血液をもとにゲノムを解析した。
    その結果、41人が生まれつきの遺伝性の病気であることがわかった。人の遺伝情報はA、T、G、Cの文字で示される30億塩基対のDNAで構成されているが、わずか1文字ないし2文字が通常と書き換わったことで病気につながったケースが大半だったという。
    また、遺伝子の異常は、親から受け継ぐケースだけでなく、突然変異によって赤ちゃんの段階で生じたケースも少なくなかった。
    原因がわかった41人のうちの20人は、筋肉や皮膚の一部を切り取って調べる「生検」をせずにすんだり、原因に応じた薬を使ったりと、より負担の少ない検査や効果的な治療につなげられたという。
    研究チームの武内俊樹・慶応大専任講師(小児科)は「ゲノム解析という最新の技術を活用して、社会で最も弱い立場にある赤ちゃんを守ることにつなげたい」と話す。研究結果は、小児科学の専門誌で公表(https://www.jpeds.com/article/S0022-3476(22)00064-6/fulltext別ウインドウで開きます)された。(編集委員・田村建二)

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  • 病気の原因がわからない赤ちゃんに対するゲノム解析の有用性を確認-全国で診断に難渋した85名の約半数で原因が判明-(プレスリリース) インターネットメディア

    慶應義塾大学医学部、大阪母子医療センター、国立成育医療研究センター、東京都立小児総合医療センター、日本医療研究開発機構(AMED))  2022年2月4日

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    日本の新生児医療は世界最高水準であることが知られていますが、それでも新生児集中治療室に入院する重症の赤ちゃんの1割程度で、病気の原因がわからないことが課題となっています。そこで、新生児科医と遺伝学研究者からなる全国チーム(代表:慶應義塾大学医学部小児科学教室の武内俊樹専任講師)は、17の高度周産期医療センターからなるネットワークを作り上げました。従来の検査法では原因を決めることができなかった85名の重症の赤ちゃんに対して、ゲノム解析という新しい方法で原因の究明を試みました。その結果、約半数(41名)が生まれつきの遺伝性疾患にかかっていることが判明しました。結果の判明したうちの約半数(20名)では、検査や治療方針の変更が行われ、このゲノム解析が新しい時代の医療技術として極めて有用であることを示しました。

    本研究成果は、2022年2月3日(東部米国時間)に、小児科学分野を代表する国際誌である『The Journal of Pediatrics』のオンライン版に掲載されました。

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  • 赤ちゃんの原因不明の病気 ゲノム解析で診断 慶応大など テレビ・ラジオ番組

    日本放送協会(NHK)  2022年2月4日

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  • 重症新生児に適切治療 新聞・雑誌

    読売新聞  2025年7月29日

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  • 赤ちゃんの原因不明の病気 全ゲノム解析で特定し治療 新聞・雑誌

    2025年3月13日

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