Genetic analysis in families with amyotrophic lateral sclerosis

肌萎缩性侧索硬化症（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。死后肌萎缩侧索硬化症患者的病理研究显示脊髓前角、脑干核和皮层的运动神经元缺失。大约10%的ALS病例是遗传性的，通常是常染色体显性性状。大约25%的家族性ALS患者检测到胞质铜锌超氧化物歧化酶（Cu/Zn SOD）基因突变，目前已知有70多种不同的突变。在这项研究中，我们使用一个日本ALS大家族进行连锁分析，以确定包含导致ALS的基因缺陷的位点。我们没有发现任何已知运动神经元疾病位点的遗传联系，现在正在进行全基因组连锁分析。此外，我们在一个患有ALS的日本家庭中发现了一种新的铜/锌SOD基因（Leu126Ser）错义突变，其中包括一名患有纯合突变的患者。纯合突变红细胞中Cu/Zn超氧化物歧化酶多肽的表达明显低于杂合突变。我们推测这种突变体Cu/Zn SOD分子的减少可能与该病例严重的临床表型有关。

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.