Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, Victoria, Australia.
Hum Mutat. 2018 Dec;39(12):1774-1787. doi: 10.1002/humu.23663. Epub 2018 Nov 8.
A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
ACTN3 基因的一个常见无效多态性（rs1815739：C>T）导致快速肌蛋白 α-辅肌动蛋白-3 中第 577 位氨基酸的精氨酸（R）被提前终止密码子（X）取代。ACTN3 p.Arg577Ter 等位基因（又名 p.R577* 或 R577X）经历了正选择，随着现代人从非洲迁移到寒冷、物种较少的欧亚气候，X 等位基因频率增加，表明在这些条件下缺乏 α-辅肌动蛋白-3可能是有益的。全世界约有 15 亿人完全缺乏 α-辅肌动蛋白-3。虽然缺乏 α-辅肌动蛋白-3会影响骨骼肌功能和代谢，但不会导致明显的肌肉疾病。α-辅肌动蛋白-3 缺乏症（ACTN3 XX 基因型）在短跑/力量表现运动员中明显不足。然而，我们和其他研究小组最近的发现表明，ACTN3 R577X 基因型在运动表现之外发挥作用，对衰老、骨骼健康以及遗传性肌肉疾病（如 McArdle 病和 Duchenne 肌肉营养不良）有影响。在这篇综述中，我们提供了有关 ACTN3 R577X 对骨骼肌功能的影响及其潜在生物学和临床意义的最新知识。我们还概述了未来的研究方向，以探索 α-辅肌动蛋白-3 在健康和患病人群中的作用。
