Identification of a causative gene for autosomal recessive familial amyotrophic lateral sclerosis

常染色体隐性遗传家族性肌萎缩侧索硬化症致病基因的鉴定

• 批准号: 22590923
• 负责人: TAKAHASHI Yuji
• 金额: $ 2.91万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590923/
• 关键词: 脳神経疾患; 遺伝子; ゲノム; 筋萎縮性側索硬化症; 連鎖解析; エクソーム解析; ゲノム解析; ALS; 変異解析

This study aims for the identification of causative genes in autosomal-recessive familial amyotrophic lateral sclerosis (AR-FALS) through a linkage analysis and mutational analysis of genes located in the candidate regions. A homozygosity mapping of three AR-FALS pedigrees revealed a candidate region overlapped among all the pedigrees. Specific primers for genomic PCR were designed for all the exons of 40 genes located in the candidate region. In addition, an array comparative genomic hybridization (array-CGH) system was designed for the detection of copy-number variations. Mutational analysis employing these systems, however, did not reveal a novel mutation. Then, a linkage analysis with the assumption of autosomal recessive mode of inheritance allowing compound heterozygous mutations was performed in one of the pedigrees with the largest pedigree size, which revealed candidate regions spanning a total length of 470 mega-bases. An exome analysis and a whole genome sequencing con ducted for a proband in the pedigree revealed an novel nonsynonymous homozygous mutation which was not registered in public databases including dbSNP, NHL-ESP or 1000 genomes. The mutation was co-segregated among family members and not found in 461 Japanese controls. Mutational analysis for 20 FALS pedigrees in whom mutations in known causative genes were excluded, however, did not reveal homozygous or compound heterozygous mutations in the gene. Mutational analysis for additional FALS pedigrees was considered to be necessary to establish the pathogenicity of the identified mutation.

本研究旨在通过对常染色体隐性遗传家族性肌萎缩侧索硬化症（AR-FALS）候选区域的基因进行连锁分析和突变分析，确定致病基因。三个AR-FALS家系的纯合性定位显示，所有家系的候选区域重叠。对候选区域内40个基因的所有外显子设计特异性引物进行基因组PCR。此外，我们还设计了一个阵列比较基因组杂交（array-CGH）系统，用于检测拷贝数变异。然而，使用这些系统的突变分析没有发现新的突变。然后，在具有最大谱系大小的一个谱系中进行了允许复合杂合突变的常染色体隐性遗传模式假设的连锁分析，其揭示了跨越总长度为470个兆碱基的候选区域。对该家系先证者进行外显子组分析和全基因组测序，发现一种新的非同义纯合突变，该突变未在公共数据库包括dbSNP、NHL-ESP或1000个基因组中登记。该突变在家庭成员中共分离，在461名日本对照中未发现。排除已知致病基因突变的20个FALS家系的突变分析没有发现该基因的纯合或复合杂合突变。认为有必要对额外的FALS家系进行突变分析，以确定所鉴定突变的致病性。

项目成果

Search for genetic risk factors and phenotypic modifiers for sporadic ALS based on extensive resequencing of causative genes for familial ALS

基于对家族性 ALS 致病基因的广泛重测序，寻找散发性 ALS 的遗传风险因素和表型修饰因子

• 发表时间: 2011
• 作者: Yuji Takahashi;Jun Goto;Shoji Tsuji
• 通讯作者: Shoji Tsuji

Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

LRRK2 的综合突变分析揭示了支持常染色体显性帕金森病关联的变异

• DOI: 10.1038/jhg.2011.79
• 发表时间: 2011
• 期刊: J Hum Genet
• 影响因子: 3.5
• 作者: Yamashita T;Deguchi K;Nagotani S;Kamiya T;Abe K;Seki N
• 通讯作者: Seki N

Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation

• DOI: 10.1136/jnnp-2011-300843
• 发表时间: 2012-02-01
• 期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
• 影响因子: 11
• 作者: Iizuka, Takahiro;Takahashi, Yuji;Sakai, Fumihiko
• 通讯作者: Sakai, Fumihiko