Department of Molecular Genetics, VIB, University of Antwerp, 2610 Antwerp, Belgium.
Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
Cold Spring Harb Perspect Med. 2018 Apr 2;8(4):a026757. doi: 10.1101/cshperspect.a026757.
Repeat expansions in the promoter region of are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the repeat, and expanded repeat size, which has been estimated between 45 and several thousand units. The role of variability in normal and expanded repeat sizes for disease risk and clinical phenotype is under debate. Different pathogenic mechanisms have been proposed, including loss of function, RNA toxicity, and dipeptide repeat (DPR) protein toxicity resulting from abnormal translation of the expanded repeat, but the major mechanism is yet unclear.
重复扩展是肌萎缩侧索硬化症（ALS）和相关 ALS/额颞叶变性（FTLD）谱疾病的最常见遗传原因。已经观察到具有重复扩展的患者之间存在显著的临床异质性，并且已经提出了不同代之间的遗传预期。已经提出了修饰临床表型的遗传因素，包括其他已知疾病基因中的遗传变异、重复扩展的基因组背景和扩展的重复大小，其估计在 45 到几千个单位之间。正常和扩展的重复大小的变异性对疾病风险和临床表型的作用仍存在争议。已经提出了不同的发病机制，包括功能丧失、RNA 毒性和由扩展重复的异常翻译引起的二肽重复（DPR）蛋白毒性，但主要机制尚不清楚。
