Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease

• Published in: Human mutation Vol. 39; no. 12; pp. 1774 - 1787
• Main Authors: Houweling, Peter J., Papadimitriou, Ioannis D., Seto, Jane T., Pérez, Laura M., Coso, Juan Del, North, Kathryn N., Lucia, Alejandro, Eynon, Nir
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01-12-2018
• Subjects: Actinin; ACTN3; ageing; Aging; Alleles; Amino acids; Arginine; athletic performance; Dystrophy; Gene frequency; Gene polymorphism; genetic variant; Genotype & phenotype; muscle disease; Muscle function; Musculoskeletal system; Nonsense mutation; Positive selection; Skeletal muscle; Stop codon; α‐actinin‐3; ageing; genetic variant; ACTN3; α-actinin-3; muscle disease; athletic performance
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23663

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.
A null polymorphism in the ACTN3 gene (rs1815739:C>T) results in a premature stop codon (X) at amino acid 577 in the fast muscle protein α‐actinin‐3. Positive selection for the X‐allele occurred as modern humans migrated out of Africa (Figure 2). Homozygosity for the X‐allele results in the absence of α‐actinin‐3 in 1.5 billion people worldwide. While not causing disease, the absence of α‐actinin‐3 may be detrimental to sprint performance and plays a role in ageing, bone health and inherited muscle diseases.