Department of Neurology, First Hospital, Shanxi Medical University, No.85, Jiefang South Street, Taiyuan, 030000, People's Republic of China.
Neurol Sci. 2022 Apr;43(4):2579-2587. doi: 10.1007/s10072-021-05634-z. Epub 2021 Sep 26.
The aim of our study was to investigate the genetic characteristics in patients with familial or young-onset amyotrophic lateral sclerosis (ALS) in a Chinese center.
Patients with familial or young-onset (age of onset < 45 years old) ALS were reviewed. The clinical data was collected. Whole-exome sequencing was performed to identify the disease-associated variants. Single-nucleotide variants and small insertions/deletions were further predicted with silico tools and compared to the Single Nucleotide Polymorphism Database, Exome Aggregation Consortium, and the 1000 Genomes Project. The evolutionary conservations were estimated, and the structures of proteins were constructed by Swiss-Model server. Immunohistochemistry was used to confirm the misfolded SOD1 protein.
Three familial ALS and 5 young-onset ALS were enrolled. Genetic analysis identified related variants of SOD1 (4/6, 66.7%), FUS (1/6, 16.7%), and NEK1 (1/6, 16.7%) in 6 patients. Three of them were familial probands (3/3, 100%), and the others were sporadic young-onset patients (3/5, 60%). NEK1 c.290G > A mutation (NM_012224.2 exon4) in a patient with familial ALS and SOD1 c.362A > G mutation (NM_000454 exon5) in a young-onset ALS patient were novel. The novel mutations were predicted to be deleterious, affected evolutionarily highly conserved amino acid residue and the formation of hydrogen bonds between the mutated site and its surrounding amino acid residues. Misfolded SOD1 protein was identified in patient with SOD1 c.362A > G mutation.
Two novel mutations were detected in our patients. Patients with familial or young-onset ALS often carried related gene mutations, and genetic sequencing should be thus routinely performed.
本研究旨在探讨中国中心家族性或早发性肌萎缩侧索硬化症（ALS）患者的遗传特征。
对家族性或早发性（发病年龄<45 岁）ALS 患者进行回顾性分析。收集临床资料。进行全外显子组测序以确定与疾病相关的变异。使用计算工具进一步预测单核苷酸变异和小插入/缺失，并与单核苷酸多态性数据库、外显子聚合联盟和 1000 基因组计划进行比较。估计进化保守性，并使用瑞士模型服务器构建蛋白质结构。使用免疫组织化学来确认错误折叠的 SOD1 蛋白。
共纳入 3 例家族性 ALS 和 5 例早发性 ALS。遗传分析在 6 例患者中发现 SOD1（4/6，66.7%）、FUS（1/6，16.7%）和 NEK1（1/6，16.7%）相关变异。其中 3 例为家族性先证者（3/3，100%），其余 3 例为散发性早发性患者（3/5，60%）。家族性 ALS 患者的 NEK1 c.290G>A 突变（NM_012224.2 外显子 4）和早发性 ALS 患者的 SOD1 c.362A>G 突变（NM_000454 外显子 5）均为新突变。新突变被预测为有害的，影响进化上高度保守的氨基酸残基以及突变位点与其周围氨基酸残基之间氢键的形成。在携带 SOD1 c.362A>G 突变的患者中鉴定出错误折叠的 SOD1 蛋白。
在我们的患者中检测到两个新突变。家族性或早发性 ALS 患者常携带相关基因突变，因此应常规进行基因测序。
