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Molecular genetic study of familial ALS in Japan

日本家族性 ALS 的分子遗传学研究

基本信息

批准号：
07457152
负责人：
ITOYAMA Yasuto
金额：
$ 3.84万
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：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457152/
关键词：
familial ALS motor neuron death Cu Zn SOD gene nitrotyrosine ALS SOD フリーラジカル

项目摘要

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.

我们报告了家族性肌萎缩侧索硬化症的临床特征，在五个日本家系中，铜/锌超氧化物歧化酶基因外显子2、4和5有四个不同的错义点突变，导致组氨酸^&lt；46&gt；被精氨酸(H46R)、亮氨酸^&lt；84&gt；由valine(L84V)、异亮氨酸^&lt；104&gt；；苯丙氨酸(I104F)和valine^&lt；148&gt；由异亮氨酸(V148I)取代。虽然进行性神经源性肌肉萎缩的特征在这些家系的患者中很常见，但每个家系的患者都有独特的临床特征。另外，对散发性肌萎缩侧索硬化症(ALS)患者和正常对照组的脊髓进行了硝基酪氨酸(NT)和铜/锌超氧化物歧化酶(SOD)免疫组织化学染色。在ALS的运动神经元中，NT的免疫反应较密集，而在对照组中未检测到或仅有极少量的NT免疫反应。肌萎缩侧索硬化症患者运动神经元上的轴突也有这种染色，而对照组则未见。相反，尽管运动神经元中的铜锌超氧化物歧化酶免疫反应较密集，但肌萎缩侧索硬化症患者的运动神经元中铜锌超氧化物歧化酶的免疫反应强度与对照组无明显差异，提示具有不同铜锌超氧化物歧化酶基因突变的家族性肌萎缩侧索硬化症具有各自的临床特征，且家族性肌萎缩侧索硬化症患者脊髓运动神经元中酪氨酸蛋白残基的硝化作用上调。