Molecular genetic study of familial ALS in Japan

我们报告了家族性肌萎缩性侧索硬化症（FALS）的临床特征，在Cu/Zn超氧化物歧化酶（SOD）基因的2、4和5外显子中有4个不同的错义点突变，导致5个日本家族的组氨酸^<46>被精氨酸（H46R）取代，亮氨酸^<84>被缬氨酸（L84V）取代，异亮氨酸^<104>被苯丙氨酸（I104F）取代，缬氨酸^<148>被异亮氨酸（V148I）取代。虽然进行性神经源性肌萎缩的特征在这些家庭的患者中是共同的，但每个家庭的患者都有自己的临床特征。此外，对散发的肌萎缩性侧索硬化症（ALS）和正常人的脊髓进行免疫组织化学检测，检测抗体为硝基酪氨酸（NT）和Cu/Zn超氧化物歧化酶（SOD）。肌萎缩侧索硬化症患者运动神经元中NT免疫反应性较强，而对照组运动神经元中NT免疫反应性较弱。肌萎缩侧索硬化症运动神经元的轴突也有染色，而对照组没有。相比之下，虽然运动神经元中Cu/Zn SOD的免疫反应性较强，但在ALS组与对照组之间没有差异。上述结果提示，不同Cu/Zn SOD基因突变的家族性ALS表现出各自的临床特征，且基因突变与家族性ALS的临床特征具有较好的相关性。此外，肌萎缩侧索硬化症脊髓运动神经元中酪氨酸蛋白残基的硝化作用上调。

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 2,4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine^<46> by arginine (H46R), leucine^<84> by valine (L84V), isoleucine^<104> by phenylalanine (I104F), and valine^<148> by isoleucine (V148I), in five Japanese families. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. In addition, spinal cords of sporadic cases with amyotrophic lateral sclerosis (ALS) and normal controls were immunohistochemically examined using antibodies for nitrotyrosine (NT) and Cu/Zn superoxide dismutase (SOD). Immunoreactivity for NT was densely detected in the motor neurons of ALS while that was not or was only minimally detected in those of controls. The staining was also found in the axons on motor neurons of ALS,but was not found in the controls. In contrast, although immunoreactivity for Cu/Zn SOD of the motor neurons was dense in the motor neurons, that was not different between the ALS and controls.These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene showed each clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.Furthermore, nitration of protein tyrosine residue is upregulated in motor neurons of the spinal cord of ALS.