Faculty Profiles - Ishiura Hiroyuki

Papers - Ishiura Hiroyuki

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Novel mutations in the PNPLA6 gene in Boucher-Neuhauser syndrome Reviewed

Kishin Koh, Fumikazu Kobayashi, Michiaki Miwa, Kazumasa Shindo, Eiji Isozaki, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama

JOURNAL OF HUMAN GENETICS 60 ( 4 ) 217 - 220 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhauser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.

DOI： 10.1038/jhg.2015.3

DNA Sequencing and Other Methods of Exonic and Genomic Analyses Reviewed

Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth Edition 77 - 85 2014.11

Language：English Publishing type：Part of collection (book) Publisher：Elsevier Inc.

DNA sequencing technologies, and the application of these technologies for exploring molecular bases of diseases as well as for clinical sequencing, are reviewed in this chapter. The methods of DNA sequencing include: 1) the Maxam-Gilbert method
2) the Sanger method
and 3) next-generation sequencing (NGS) technologies. In addition, other technologies including fluorescence in situ hybridization (FISH) analysis, microarray-based comparative genomic hybridization (array CGH) analysis, polymerase chain reaction (PCR)-based methods (quantitative PCR analysis, multiplex ligation-dependent probe amplification (MLPA) analysis, PCR fragment analysis, and repeat-primed PCR analysis), and Southern blot hybridization analysis are also used to analyze alterations of structures of DNA molecules. Among these, in particular, NGS technologies are currently revolutionizing the field of molecular genetics research of diseases. Comprehensive genome sequence analyses employing NGS technologies have demonstrated excellent competence to identify molecular bases of diseases with Mendelian-trait as well as those with complex trait. NGS technologies are also being increasingly applied for clinical sequencing to provide molecular diagnoses of diseases.

DOI： 10.1016/B978-0-12-410529-4.00006-1

Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation Reviewed

Haruo Shimazaki, Junko Honda, Tametou Naoi, Michito Namekawa, Imaharu Nakano, Masahide Yazaki, Katsuya Nakamura, Kunihiro Yoshida, Shu-ichi Ikeda, Hiroyuki Ishiura, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yoshihisa Takiyama

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 85 ( 9 ) 1024 - 1028 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

Background Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy.
Methods This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample.
Results We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chediak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency.
Conclusions We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

DOI： 10.1136/jnnp-2013-306981

A Recurrent De Novo FAM111A Mutation Causes Kenny-Caffey Syndrome Type 2 Reviewed

Tsuyoshi Isojima, Koichiro Doi, Jun Mitsui, Yoichiro Oda, Etsuro Tokuhiro, Akihiro Yasoda, Tohru Yorifuji, Reiko Horikawa, Jun Yoshimura, Hiroyuki Ishiura, Shinichi Morishita, Shoji Tsuji, Sachiko Kitanaka

JOURNAL OF BONE AND MINERAL RESEARCH 29 ( 4 ) 992 - 998 2014.4

Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing Reviewed

Koichiro Doi, Taku Monjo, Pham H. Hoang, Jun Yoshimura, Hideaki Yurino, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Yaeko Ichikawa, Jun Goto, Shoji Tsuji, Shinichi Morishita

BIOINFORMATICS 30 ( 6 ) 815 - 822 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Motivation: Long expansions of short tandem repeats (STRs), i.e. DNA repeats of 2-6 nt, are associated with some genetic diseases. Cost-efficient high-throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100bp, the typical length of short reads.
Results: We propose ab initio procedures for sensing and locating long STRs promptly by using the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in 11 SCA31 samples using SMRT TM sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads.

DOI： 10.1093/bioinformatics/btt647

Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan Reviewed

Megumi Yamada, Masaki Tanaka, Mari Takagi, Seiju Kobayashi, Yoshiharu Taguchi, Shutaro Takashima, Kortaro Tanaka, Tetsuo Touge, Hiroyuki Hatsuta, Shigeo Murayama, Yuichi Hayashi, Masayuki Kaneko, Hiroyuki Ishiura, Jun Mitsui, Naoki Atsuta, Gen Sobue, Nobuyuki Shimozawa, Takashi Inuzuka, Shoji Tsuji, Isao Hozumi

NEUROLOGY 82 ( 8 ) 705 - 712 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objective:To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan.Methods:We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed.Results:Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family.Conclusion:SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.

DOI： 10.1212/WNL.0000000000000143

Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12 Reviewed

Guida Landoure, Peng-Peng Zhu, Charles M. Lourenco, Janel O. Johnson, Camilo Toro, Katherine V. Bricceno, Carlo Rinaldi, Katherine G. Meilleur, Modibo Sangare, Oumarou Diallo, Tyler M. Pierson, Hiroyuki Ishiura, Shoji Tsuji, Nichole Hein, John K. Fink, Marion Stoll, Garth Nicholson, Michael A. Gonzalez, Fiorella Speziani, Alexandra Duerr, Giovanni Stevanin, Leslie G. Biesecker, John Accardi, Dennis M. D. Landis, William A. Gahl, Bryan J. Traynor, Wilson Marques, Stephan Zuechner, Craig Blackstone, Kenneth H. Fischbeck, Barrington G. Burnett

HUMAN MUTATION 34 ( 10 ) 1357 - 1360 2013.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. Published 2013 Wiley Periodicals, Inc.

DOI： 10.1002/humu.22378

Exome analysis reveals a Japanese family with spinocerebellar ataxia, autosomal recessive 1 Reviewed

Yaeko Ichikawa, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Shunsuke Kobayashi, Hiroshi Takuma, Ichiro Kanazawa, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Shoji Tsuji

JOURNAL OF THE NEUROLOGICAL SCIENCES 331 ( 1-2 ) 158 - 160 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Spinocerebellar ataxia autosomal recessive 1 (SCAR1/AOA2) is clinically characterized by an early-onset progressive cerebellar ataxia with axonal neuropathy, ocular motor apraxia, and elevation of serum alpha-fetoprotein level. The disorder is caused by mutations in senataxin (SETX) gene. Here, we report a Japanese SCAR1/AOA2 family with a homozygous nonsense mutation (p.Q1441X) of SETX that was identified by exome sequencing. The family was previously reported as early-onset ataxia of undetermined cause. The present study emphasized the role of whole exome-sequence analysis to establish the molecular diagnosis of neurodegenerative disease presenting with diverse clinical presentations. (C) 2013 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2013.05.018

[Present efforts in the medical genome center at the University of Tokyo Hospital]. Reviewed

Mitsui J, Ishiura H, Tsuji S

Brain and nerve = Shinkei kenkyu no shinpo 65 ( 3 ) 247 - 255 2013.3

Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients Reviewed

Atsushi Ishii, Yoshiaki Saito, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Hidee Arai, Sumimasa Yamashita, Sadami Kimura, Hirokazu Oguni, Shinichi Morishita, Shoji Tsuji, Masayuki Sasaki, Shinichi Hirose

PLoS ONE 8 ( 2 ) e56120 2013.2

Language：English Publishing type：Research paper (scientific journal)

Background: Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. Principal Findings: A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. Interpretation: Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC. © 2013 Ishii et al.

DOI： 10.1371/journal.pone.0056120

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG Reviewed

Hiroyuki Ishiura, Shoji Tsuji

Clinical Neurology 53 ( 11 ) 1203 - 1205 2013

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Societas Neurologica Japonica

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C&gt
T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

DOI： 10.5692/clinicalneurol.53.1203

A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55) Reviewed

Haruo Shimazaki, Yoshihisa Takiyama, Hiroyuki Ishiura, Chika Sakai, Yuichi Matsushima, Hideyuki Hatakeyama, Junko Honda, Kumi Sakoe, Tametou Naoi, Michito Namekawa, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yu-ichi Goto, Imaharu Nakano

JOURNAL OF MEDICAL GENETICS 49 ( 12 ) 777 - 784 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

Background Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy.
Methods The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control.
Results We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV.
Conclusions This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

DOI： 10.1136/jmedgenet-2012-101212

CSF1R Mutations Identified in Three Families With Autosomal Dominantly Inherited Leukoencephalopathy Reviewed

Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Koichiro Higasa, Jun Yoshimura, Taro L. Saito, Budrul Ahsan, Yuji Takahashi, Jun Goto, Atsushi Iwata, Yuki Niimi, Yuuichi Riku, Yoji Goto, Kazuo Mano, Mari Yoshida, Shinichi Morishita, Shoji Tsuji

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 159B ( 8 ) 951 - 957 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Genetic and phenotypic heterogeneities are considerably high in adult-onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult-onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult-onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy-proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R was well as cross-species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.b.32100

Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population Reviewed

Hiroya Naruse, Yuji Takahashi, Tameko Kihira, Sohei Yoshida, Yasumasa Kokubo, Shigeki Kuzuhara, Hiroyuki Ishiura, Masaharu Amagasa, Shigeo Murayama, Shoji Tsuji, Jun Goto

AMYOTROPHIC LATERAL SCLEROSIS 13 ( 6 ) 562 - 566 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c. 481G > A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population.

DOI： 10.3109/17482968.2012.684213

Adult-onset Alexander disease with an R66Q mutation in GFAP presented with severe vocal cord paralysis during sleep Reviewed

Ayumi Hida, Hiroyuki Ishiura, Noritoshi Arai, Hisayo Fukuoka, Kanehiro Hasuo, Jun Goto, Yoshikazu Uesaka, Shoji Tsuji, Sousuke Takeuchi

JOURNAL OF NEUROLOGY 259 ( 10 ) 2234 - 2236 2012.10

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study Reviewed

Elisa Majounie, Alan E. Renton, Kin Mok, Elise G. P. Dopper, Adrian Waite, Sara Rollinson, Adrian Chio, Gabriella Restagno, Nayia Nicolaou, Javier Simon-Sanchez, John C. van Swieten, Yevgeniya Abramzon, Janel O. Johnson, Michael Sendtner, Roger Pamphlett, Richard W. Orrell, Simon Mead, Katie C. Sidle, Henry Houlden, Jonathan D. Rohrer, Karen E. Morrison, Hardev Pall, Kevin Talbot, Olaf Ansorge, Dena G. Hernandez, Sampath Arepalli, Mario Sabatelli, Gabriele Mora, Massimo Corbo, Fabio Giannini, Andrea Calvo, Elisabet Englund, Giuseppe Borghero, Gian Luca Foris, Anne M. Remes, Hannu Laaksovirta, Leo McCluskey, John Q. Trojanowski, Vivianna M. Van Deerlin, Gerard D. Schellenberg, Michael A. Nalls, Vivian E. Drory, Chin-Song Lu, Tu-Hsueh Yeh, Hiroyuki Ishiura, Yuji Takahashi, Shoji Tsuji, Isabelle Le Ber, Alexis Brice, Carsten Drepper, Nigel Williams, Janine Kirby, Pamela Shaw, John Hardy, Pentti J. Tienari, Peter Heutink, Huw R. Morris, Stuart Pickering-Brown, Bryan J. Traynor

LANCET NEUROLOGY 11 ( 4 ) 323 - 330 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.

DOI： 10.1016/S1474-4422(12)70043-1

Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12 Reviewed

Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison, Carla Babalini, Michela D'Aloia, Pasqua Montieri, Rebecca Schuele, Hiroyuki Ishiura, Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon, Tine Deconinck, Jia Huang, Giorgio Bernardi, Jeffery M. Vance, Mark T. Rogers, Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Schoels, Antonio Orlacchio, Evan Reid, Stephan Zuechner

JOURNAL OF CLINICAL INVESTIGATION 122 ( 2 ) 538 - 544 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.

DOI： 10.1172/JCI60560

Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease Reviewed

Meiko Hashimoto Maeda, Jun Mitsui, Bing-Wen Soong, Yuji Takahashi, Hiroyuki Ishiura, Shin Hayashi, Yuichiro Shirota, Yaeko Ichikawa, Hideyuki Matsumoto, Makoto Arai, Tomoko Okamoto, Sahoko Miyama, Jun Shimizu, Johji Inazawa, Jun Goto, Shoji Tsuji

ANNALS OF NEUROLOGY 71 ( 1 ) 84 - 92 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objective: On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot-Marie-Tooth disease (CMT) whose responsible genes remain undefined. Methods: A family with 6 affected members in 3 consecutive generations, presenting with motor and sensory demyelinating polyneuropathy, was investigated. Characteristic clinical features in this pedigree include Adie pupils and substantial intrafamilial variability in the age at onset, electrophysiological findings, and clinical severity. Nucleotide sequence analyses of PMP22, MPZ, or GJB1 and gene dosage study of PMP22 did not reveal causative mutations. Hence, we applied a custom- designed array for comparative genomic hybridization ( CGH) analysis to conduct a comprehensive screening of copy number mutations involving any of the known causative genes for CMT other than PMP22. Results: The array CGH analyses revealed increased gene dosage involving the whole MPZ, and the flanking genes of SDHC and C1orf192. The gene dosage is estimated to be 5 copies. This mutation showed complete cosegregation with the disease phenotype in this pedigree. Interpretation: The increased gene dosage of MPZ and increased expression level of MPZ mRNA emphasize the important role of the dosage of the MPZ protein in the functional integrity of peripheral nerve myelin in humans, and provide a new insight into the pathogenic mechanisms underlying CMT.

DOI： 10.1002/ana.22658

Hypertrophic Pachymeningitis and Tracheobronchial Stenosis in IgG4-related Disease: Case Presentation and Literature Review Reviewed

Hiroyuki Yamashita, Yuko Takahashi, Hiroyuki Ishiura, Toshikazu Kano, Hiroshi Kaneko, Akio Mimori

INTERNAL MEDICINE 51 ( 8 ) 935 - 941 2012

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

Immunoglobulin G4 (IgG4)-related disease is a distinctive mass-forming disorder with frequent systemic involvement, most commonly in the pancreas, salivary glands and lacrimal glands. A few cases of dural involvement and one case of central airway stenosis have also been described. We report here a rare case of IgG4-related disease with intracranial hypertrophic pachymeningitis and irregular tracheobronchial stenosis. We review four previously reported cases of IgG4-related pachymeningitis. We currently lack international standards for the diagnosis of extrapancreatic IgG4-related disease. Based on the findings of the present case and those reported previously, we discuss the distinctive features of IgG4-related pachymeningitis.

DOI： 10.2169/internalmedicine.51.6604

Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5 Reviewed

Takashi Matsukawa, Xuemin Wang, Rui Liu, Noel C. Wortham, Yuko Onuki, Akatsuki Kubota, Ayumi Hida, Hisatomo Kowa, Yoko Fukuda, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Shigeki Aoki, Shunya Takizawa, Jun Shimizu, Jun Goto, Christopher G. Proud, Shoji Tsuji

NEUROGENETICS 12 ( 3 ) 259 - 261 2011.8

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