研究者詳細 - 石浦　浩之

Novel mutation in the membrane metalloendopeptidase gene in a patient with the autosomal recessive form of Charcot-Marie-Tooth disease 査読

Ishiura Hiroyuki, Mitsui Jun, Yoshimura Jun, Doi Koichiro, Morishita Shinichi, Hamada Masashi, Goto Jun, Tsuji Shoji

NEUROLOGY AND CLINICAL NEUROSCIENCE 5 ( 4 ) 124 - 126 2017年7月

Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations 査読

Jun Mitsui, Ken Koguchi, Toshimitsu Momose, Miwako Takahashi, Takashi Matsukawa, Tsutomu Yasuda, Shin-ichi Tokushige, Hiroyuki Ishiura, Jun Goto, Shigeaki Nakazaki, Tomoyoshi Kondo, Hidefumi Ito, Yorihiro Yamamoto, Shoji Tsuji

CEREBELLUM 16 ( 3 ) 664 - 672 2017年6月

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

We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q(10) levels in cerebrospinal fluid as well as in plasma. The patient was at the advanced stage of MSA, and the various scores of clinical rating scales remained stable without changes during the 3 years. The cerebral metabolic ratio of oxygen measured by O-15(2) PET, however, increased by approximately 30% after administration of ubiquinol, suggesting that ubiquinol can improve mitochondrial oxidative metabolism in the brain. It also suggests the therapeutic potential of ubiquinol for patients with MSA with COQ2 mutations. Further clinical trials of administration of high-dose ubiquinol to MSA patients are warranted.

DOI： 10.1007/s12311-017-0846-9

Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype 査読

Toru Yamashita, Jun Mitsui, Nobuyuki Shimozawa, Shigeo Takashima, Hiroshi Umemura, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Takashi Matsukawa, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Koji Abe

JOURNAL OF THE NEUROLOGICAL SCIENCES 375 424 - 429 2017年4月

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 SCIENCE BV

Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2017.02.058

TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy 査読

Toshio Ikeda, Akihiko Nakahara, Rie Nagano, Maiko Utoyama, Megumi Obara, Hiroshi Moritake, Tamayo Uechi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Naoya Kenmochi, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroyuki Nunoi

JOURNAL OF HUMAN GENETICS 62 ( 4 ) 473 - 480 2017年4月

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

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.

DOI： 10.1038/jhg.2016.149

Authors' response to "Compound heterozygous Fukutin mutation-related non-compaction" by Finsterer and Zarrouk-Mahjoub 査読

Eisuke Amiya, Hiroyuki Morita, Hiroyuki Ishiura, Shoji Tsuji, Issei Komuro

INTERNATIONAL JOURNAL OF CARDIOLOGY 233 102 - 102 2017年4月

Novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. 査読国際誌

Harigaya Y, Matsukawa T, Fujita Y, Mizushima K, Ishiura H, Mitsui J, Morishita S, Shoji M, Ikeda Y, Tsuji S

Neurology. Genetics 3 ( 2 ) e138 2017年4月

Slowly progressive D-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing 査読

Takashi Matsukawa, Kagari Mano Koshi, Jun Mitsui, Taro Bannai, Miho Kawabe, Hiroyuki Ishiura, Yasuo Terao, Jun Shimizu, Keiko Murayama, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Jun Goto

JOURNAL OF THE NEUROLOGICAL SCIENCES 372 6 - 10 2017年1月

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 SCIENCE BV

D-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/jjns.2016.11.009

Novel mutation in the SOD1 gene in a patient with early-onset, rapidly progressive amyotrophic lateral sclerosis. 査読

kazaki M, Suzuki H, Takahashi Y, Ishiura H, Goto J, Hirano M, Saigoh K, Nakamura Y, Naruse H, Mitsui J, Tsuji S, Kusunoki S

Neurol Clin Neurosci 5 189 - 191 2017年

Fukutin gene mutations that cause left ventricular noncompaction 査読

Eisuke Amiya, Hiroyuki Morita, Masaru Hatanoa, Daisuke Nitta, Yumiko Hosoya, Hisataka Maki, Yoshihiro Motozawa, Naoko Sato, Hiroyuki Ishiura, Satoe Numakura, Yukako Shintani, Koichiro Kinugawa, Norifumi Takeda, Jun Shimizu, Shoji Tsuji, Issei Komuro

INTERNATIONAL JOURNAL OF CARDIOLOGY 222 727 - 729 2016年11月

Modeling neurological diseases with induced pluripotent cells reprogrammed from immortalized lymphoblastoid cell lines 査読

Koki Fujimori, Toshiki Tezuka, Hiroyuki Ishiura, Jun Mitsui, Koichiro Doi, Jun Yoshimura, Hirobumi Tada, Takuya Matsumoto, Miho Isoda, Ryota Hashimoto, Nubutaka Hattori, Takuya Takahashi, Shinichi Morishita, Shoji Tsuji, Wado Akamatsu, Hideyuki Okano

MOLECULAR BRAIN 9 ( 1 ) 88 2016年10月

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

Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs. However, it remains unclear whether patient's LCL-derived iPSCs (LiPSCs) can function as a disease model. Therefore, we generated Parkinson's disease patient-specific LiPSCs and evaluated their utility as tools for modeling neurological diseases. We established iPSCs from two LCL clones, which were derived from a healthy donor and a patient carrying PARK2 mutations, by using existing non-integrating episomal protocols. Whole genome sequencing (WGS) and comparative genomic hybridization (CGH) analyses showed that the appearance of somatic variations in the genomes of the iPSCs did not vary substantially according to the original cell types (LCLs, T-cells and fibroblasts). Furthermore, LiPSCs could be differentiated into functional neurons by using the direct neurosphere conversion method (dNS method), and they showed several Parkinson's disease phenotypes that were similar to those of DF-iPSCs. These data indicate that the global LCL repositories can be used as a resource for generating iPSCs and disease models. Thus, LCLs are the powerful tools for generating iPSCs and modeling neurological diseases.

DOI： 10.1186/s13041-016-0267-6

AgIn: measuring the landscape of CpG methylation of individual repetitive elements 査読

Yuta Suzuki, Jonas Korlach, Stephen W. Turner, Tatsuya Tsukahara, Junko Taniguchi, Wei Qu, Kazuki Ichikawa, Jun Yoshimura, Hideaki Yurino, Yuji Takahashi, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroyuki Takeda, Shinichi Morishita

BIOINFORMATICS 32 ( 19 ) 2911 - 2919 2016年10月

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

Motivation: Determining the methylation state of regions with high copy numbers is challenging for second-generation sequencing, because the read length is insufficient to map reads uniquely, especially when repetitive regions are long and nearly identical to each other. Single-molecule real-time (SMRT) sequencing is a promising method for observing such regions, because it is not vulnerable to GC bias, it produces long read lengths, and its kinetic information is sensitive to DNA modifications.
Results: We propose a novel linear-time algorithm that combines the kinetic information for neighboring CpG sites and increases the confidence in identifying the methylation states of those sites. Using a practical read coverage of similar to 30-fold from an inbred strain medaka (Oryzias latipes), we observed that both the sensitivity and precision of our method on individual CpG sites were -93.7%. We also observed a high correlation coefficient (R=0.884) between our method and bisulfite sequencing, and for 92.0% of CpG sites, methylation levels ranging over [0,1] were in concordance within an acceptable difference 0.25. Using this method, we characterized the landscape of the methylation status of repetitive elements, such as LINEs, in the human genome, thereby revealing the strong correlation between CpG density and hypomethylation and detecting hypomethylation hot spots of LTRs and LINEs. We uncovered the methylation states for nearly identical active transposons, two novel LINE insertions of identity similar to 99% and length 6050 base pairs (bp) in the human genome, and 16 Tol2 elements of identity > 99.8% and length 4682 bp in the medaka genome.

DOI： 10.1093/bioinformatics/btw360

Novel COL6A2 mutation in a case of limb girdle muscular dystrophy phenotype with autosomal recessive inheritance 査読

Mitsui Jun, Ishiura Hiroyuki, Yoshimura Jun, Doi Koichiro, Morishita Shinichi, Shoji Hiroshi, Arimori Yojiro, Matsumoto Takafumi, Shimizu Jun, Tsuji Shoji

NEUROLOGY AND CLINICAL NEUROSCIENCE 4 ( 5 ) 189 - 191 2016年9月

Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy 査読

Jun Mitsui, Takashi Matsukawa, Tsutomu Yasuda, Hiroyuki Ishiura, Shoji Tsuji

JAMA NEUROLOGY 73 ( 8 ) 977 - 980 2016年8月

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

IMPORTANCE Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA.
OBJECTIVE To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.
DESIGN, SETTING, AND PARTICIPANTS We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level.
MAIN OUTCOMES AND MEASURES Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype.
RESULTS Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] mu g/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) mu g/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02).
CONCLUSIONS AND RELEVANCE Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

DOI： 10.1001/jamaneurol.2016.1325

Human genetic variation database, a reference database of genetic variations in the Japanese population. 査読国際誌

Koichiro Higasa, Noriko Miyake, Jun Yoshimura, Kohji Okamura, Tetsuya Niihori, Hirotomo Saitsu, Koichiro Doi, Masakazu Shimizu, Kazuhiko Nakabayashi, Yoko Aoki, Yoshinori Tsurusaki, Shinichi Morishita, Takahisa Kawaguchi, Osuke Migita, Keiko Nakayama, Mitsuko Nakashima, Jun Mitsui, Maiko Narahara, Keiko Hayashi, Ryo Funayama, Daisuke Yamaguchi, Hiroyuki Ishiura, Wen-Ya Ko, Kenichiro Hata, Takeshi Nagashima, Ryo Yamada, Yoichi Matsubara, Akihiro Umezawa, Shoji Tsuji, Naomichi Matsumoto, Fumihiko Matsuda

Journal of human genetics 61 ( 6 ) 547 - 53 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

DOI： 10.1038/jhg.2016.12

Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8 査読

Yuta Ichinose, Kishin Koh, Megumi Fukumoto, Nobuo Yamashiro, Fumikazu Kobayashi, Michiaki Miwa, Takamura Nagasaka, Kazumasa Shindo, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama

CLINICAL NEUROLOGY AND NEUROSURGERY 144 36 - 38 2016年5月

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 SCIENCE BV

Exome sequencing revealed a novel missense mutation (c.2152G > A, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world. We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.clineuro.2016.02.031

Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2 査読

Yujiro Higuchi, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Satoshi Ishihara, Hajime Tanabe, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Ryuichi Ohkubo, Saeko Inamizu, Wataru Shiraishi, Ryo Yamasaki, Yasumasa Ohyagi, Jun-ichi Kira, Yasushi Oya, Hayato Yabe, Noriko Nishikawa, Shinsuke Tobisawa, Nozomu Matsuda, Masayuki Masuda, Chiharu Kugimoto, Kazuhiro Fukushima, Satoshi Yano, Jun Yoshimura, Koichiro Doi, Masanori Nakagawa, Shinichi Morishita, Shoji Tsuji, Hiroshi Takashima

ANNALS OF NEUROLOGY 79 ( 4 ) 659 - 672 2016年4月

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-BLACKWELL

ObjectiveThe objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT.
MethodsTo efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.
ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (A)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess A in Pittsburgh compound-B positron emission tomography imaging.
InterpretationOur results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659-672

DOI： 10.1002/ana.24612

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia 査読

Kelly L. Williams, Simon Topp, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie Farrawell, Caroline Vance, Xun Hu, Alessandra Chesi, Claire S. Leblond, Albert Lee, Stephanie L. Rayner, Vinod Sundaramoorthy, Carol Dobson-Stone, Mark P. Molloy, Marka van Blitterswijk, Dennis W. Dickson, Ronald C. Petersen, Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Cyril Pottier, Emily Don, Claire Winnick, Emily P. McCann, Alison Hogan, Hussein Daoud, Annie Levert, Patrick A. Dion, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Jason Kost, Cinzia Gellera, Athina Soragia Gkazi, Jack Miller, Joanne Stockton, William S. Brooks, Karyn Boundy, Meraida Polak, Jose Luis Munoz-Blanco, Jesus Esteban-Perez, Alberto Rabano, Orla Hardiman, Karen E. Morrison, Nicola Ticozzi, Vincenzo Silani, Jacqueline de Belleroche, Jonathan D. Glass, John B. J. Kwok, Gilles J. Guillemin, Roger S. Chung, Shoji Tsuji, Robert H. Brown, Alberto Garcia-Redondo, Rosa Rademakers, John E. Landers, Aaron D. Gitler, Guy A. Rouleau, Nicholas J. Cole, Justin J. Yerbury, Julie D. Atkin, Christopher E. Shaw, Garth A. Nicholson, Ian P. Blair

NATURE COMMUNICATIONS 7 11253 2016年4月

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

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

DOI： 10.1038/ncomms11253

A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia A Broadened Spectrum of SCA34 査読

Kokoro Ozaki, Hiroshi Doi, Jun Mitsui, Nozomu Sato, Yoichiro Iikuni, Takamasa Majima, Kiyomi Yamane, Takashi Irioka, Hiroyuki Ishiura, Koichiro Doi, Shinichi Morishita, Miwa Higashi, Teruhiko Sekiguchi, Kazuo Koyama, Naohisa Ueda, Yoshiharu Miura, Satoko Miyatake, Naomichi Matsumoto, Takanori Yokota, Fumiaki Tanaka, Shoji Tsuji, Hidehiro Mizusawa, Kinya Ishikawa

JAMA NEUROLOGY 72 ( 7 ) 797 - 805 2015年7月

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

IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.
OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations.
DESIGN, SETTING, AND PARTICIPANTS Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997.
MAIN OUTCOMES AND MEASURES Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.
RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families.
CONCLUSIONS AND RELEVANCE Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

DOI： 10.1001/jamaneurol.2015.0610