Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
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DOI：
10.1016/s1474-4422(17)30401-5
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发表时间：
2018-01
期刊：
影响因子：
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通讯作者：
Traynor BJ
中科院分区：
文献类型：
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作者：
Chia R;Chiò A;Traynor BJ
肌萎缩性侧索硬化症（ALS）病程迅速，由于其病理生理学尚不清楚，很少有有效的治疗方法。遗传学研究旨在了解ALS的潜在机制并确定潜在的治疗靶点。第一个与ALS相关的基因是SOD1，于1993年被发现，到2014年初，已有20多个基因被确定为ALS的病因或与ALS高度相关。这些基因发现已经确定了关键的疾病途径，这些途径在治疗上是可测试的，可能会导致开发出更好的治疗ALS患者的方法。自2014年以来，又有7个基因与ALS相关（MATR3、CHCHD10、TBK1、TUBA4A、NEK1、C21orf2和CCNF），所有这些基因都是通过全基因组关联研究、全基因组研究或外显子组测序技术确定的。七个新基因中的每一个都编码与已知参与ALS的一种或多种分子途径相关的蛋白质。这些途径包括由于蛋白质聚集异常或蛋白质清除途径缺陷导致的整体蛋白质稳态功能障碍、线粒体功能障碍、RNA代谢改变、细胞骨架完整性受损、轴突运输动力学改变以及由于DNA修复缺陷导致的DNA损伤积累。由于这些新基因与ALS中涉及的其他基因具有共同的疾病通路，针对这些通路的治疗方法可能对按基因型分层的广泛患者群体有用。然而，这些新基因的作用尚未在动物模型中进行研究，这将是将这些发现转化为临床实践的关键一步。这7个新基因的鉴定对于揭示ALS的分子机制具有重要意义。然而，我们对导致ALS的原因的理解并不完整，进一步的基因研究将提供有关其原因的更多细节。增加的遗传知识也将确定潜在的治疗靶点，并可能导致针对ALS患者的个性化药物的发展。当基因组测序成为疾病诊断和管理的常规和不可或缺的一部分时，这些发展将对临床实践产生直接影响。
The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS. Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.