The genetics of amyotrophic lateral sclerosis: current insights.
The genetics of amyotrophic lateral sclerosis: current insights.
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DOI：
10.2147/dnnd.s84956
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发表时间：
2016
影响因子：
4
通讯作者：
Kirby J
中科院分区：
文献类型：
--
作者：
Alsultan AA;Waller R;Heath PR;Kirby J
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其导致来自运动皮层、脑干和脊髓的上运动神经元和下运动神经元的丧失。虽然大多数病例是散发性的，但约10%显示家族遗传。ALS通常以常染色体显性方式遗传，尽管常染色体隐性遗传和X连锁遗传确实存在。到目前为止，已经确定了26个基因座的24个基因;这些基因座包括与ALS和额颞叶痴呆-ALS相关的基因座，其中家族谱系包含患有额颞叶痴呆伴/不伴ALS的个体。迄今为止，家族性ALS（FALS）最常见的遗传原因是C9 ORF 72基因中存在六核苷酸重复扩增（39.3%）和SOD 1，TARDBP和FUS突变，频率分别为12%-23.5%，5%和4.1%。然而，随着小家族谱系的下一代测序的使用越来越多，这导致越来越多的基因与ALS相关。本文综述了ALS的遗传学研究进展，并对与这些基因相关的致病机制进行了综述。目前已经建立了一些与之相关的通路，包括RNA加工、自噬和泛素-蛋白酶体系统的蛋白质降解通路，以及蛋白质运输和细胞骨架功能。阐明遗传学在FALS和散发性ALS中的作用对于理解导致运动神经元损失的后续细胞失调至关重要，以便开发未来有效的治疗策略。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in loss of the upper and lower motor neurons from motor cortex, brainstem, and spinal cord. While the majority of cases are sporadic, approximately 10% show familial inheritance. ALS is usually inherited in an autosomal dominant manner, although autosomal recessive and X-linked inheritance do occur. To date, 24 of the genes at 26 loci have been identified; these include loci linked to ALS and to frontotemporal dementia-ALS, where family pedigrees contain individuals with frontotemporal dementia with/without ALS. The most commonly established genetic causes of familial ALS (FALS) to date are the presence of a hexanucleotide repeat expansion in the C9ORF72 gene (39.3% FALS) and mutation of SOD1, TARDBP, and FUS, with frequencies of 12%–23.5%, 5%, and 4.1%, respectively. However, with the increasing use of next-generation sequencing of small family pedigrees, this has led to an increasing number of genes being associated with ALS. This review provides a comprehensive review on the genetics of ALS and an update of the pathogenic mechanisms associated with these genes. Commonly implicated pathways have been established, including RNA processing, the protein degradation pathways of autophagy and ubiquitin–proteasome system, as well as protein trafficking and cytoskeletal function. Elucidating the role genetics plays in both FALS and sporadic ALS is essential for understanding the subsequent cellular dysregulation that leads to motor neuron loss, in order to develop future effective therapeutic strategies.