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Genetic analysis in families with amyotrophic lateral sclerosis

肌萎缩侧索硬化症家族的遗传分析

基本信息

批准号：
11470144
负责人：
ITOYAMA Yasuto
金额：
$ 8.64万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470144/
关键词：
Autosomal dominant amyotrophic lateral sclerosis linkage analysis familial motor neuron motor neuron disease

项目摘要

Amyotrophic lateral screlosis (ALS) is a fatal neurodegenerative disease caused by selective death of motor neurons. Pathological studies of postmortem ALS patients revealed motor neuron loss in the anterior horn of the spinal cord, the nucleus of brainstem and the cortex. Approximately 10% of cases of ALS are inherited, usually as an autosomal dominant trait. Mutations of the cytosolic cupper-zinc superoxide dismutase (Cu/Zn SOD) gene were detected in about 25% of patients with familial ALS and until now more than 70 different mutations are known. In this study, we carry out a linkage analysis using a large Japanese family with ALS to identify loci that contain genes whose defects cause ALS.We did not detect any genetic linkage to the known locus of motor neuron diseases and now going on a genome-wide linkage analysis. In addition, we identified a novel missense mutation of the Cu/Zn SOD gene (Leu126Ser) in a Japanese family with ALS that included a patient with the homozygous mutation. The expression of the Cu/Zn SOD polypeptide in erythrocytes was markedly reduced in the case with the homozygous mutation compared to those with the heterozygous mutation. We speculated that this reduction of the mutant Cu/Zn SOD molecule may be related to the severe clinical phenotype of the case.

肌萎缩侧索硬化症（Amyotrophic lateral screlosis，ALS）是一种由运动神经元选择性死亡引起的致死性神经退行性疾病。ALS患者死后病理学检查显示脊髓前角、脑干核团和皮质运动神经元丢失。大约10%的ALS病例是遗传的，通常是常染色体显性遗传。在大约25%的家族性ALS患者中检测到细胞溶质铜锌超氧化物歧化酶（Cu/Zn SOD）基因突变，迄今为止已知有70多种不同的突变。在这项研究中，我们进行了连锁分析，使用一个大的日本家庭与ALS，以确定位点，包含基因的缺陷导致ALS。我们没有检测到任何遗传连锁的已知位点的运动神经元疾病，现在正在进行全基因组的连锁分析。此外，我们确定了一个新的错义突变的铜/锌SOD基因（Leu 126 Ser）在日本的ALS家族，其中包括一个纯合突变的患者。与杂合突变相比，纯合突变的红细胞中Cu/Zn SOD多肽的表达显著降低。我们推测突变型Cu/Zn SOD分子的这种减少可能与该病例的严重临床表型有关。