ACTN3 Deficiency
North et al. (1999) identified a C-to-T transition at nucleotide 1747 (rs1815739) in exon 16 of the ACTN3 gene, which resulted in a stop codon replacing the arg at residue 577 (R577X). This mutation resulted in no protein detectable by Western blot (ACTN3 deficiency; 617749). Sixteen percent of the world population is predicted to be homozygous for this mutation. No disease phenotype is associated; therefore, North et al. (1999) suggested that the ACTN3 gene is functionally redundant in humans.
Mills et al. (2001) genotyped nonhuman primates and concluded that the R577X null mutation most likely arose in humans.
Suminaga et al. (2000) found an allele frequency of 0.49 for the 1747C-T polymorphism in Japanese. Although the incidence (24.2%) of congenital deficiency of alpha-actinin-3 was high, no evidence could be found that the homozygous state modified the dystrophinopathies Duchenne muscular dystrophy (310200) and Becker muscular dystrophy (300376).
Sprinting Performance
Yang et al. (2003) found that the R577X genotype is associated with human elite athletic performance. Both male and female elite sprint athletes had significantly higher frequencies of the 577R allele than did controls. In female sprint and endurance athletes there was a higher than expected number of R577X heterozygotes among sprint athletes and lower than expected numbers among endurance athletes. The lack of a similar effect in males suggested that the ACTN3 genotype affects athletic performance differently in males and females. The differential effects in sprint and endurance athletes suggested that the R577X polymorphism may have been maintained in the human population by balancing natural selection.
Niemi and Majamaa (2005) determined the ACTN3 R577X genotype in 52 elite Finnish endurance and 89 sprint athletes and found that the frequency of the XX genotype was higher and RR lower among the endurance athletes, and that none of the top Finnish sprinters had the XX genotype.
The association of the R577X polymorphism with elite athlete status and human muscle performance suggests that ACTN3 deficiency influences the function of fast muscle fibers. MacArthur et al. (2007) showed that loss of ACTN3 expression in a knockout mouse model resulted in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, they demonstrated that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. They proposed that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.
In a study of 992 Greek adolescent boys and girls, Moran et al. (2007) found a significant association between the ACTN3 R577X polymorphism and 40 meter sprint times in males (p = 0.003) that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive fashion. The R577X polymorphism was not associated with other predominantly strength/power-related or endurance phenotypes.
Saunders et al. (2007) genotyped 457 Caucasian male triathletes who completed the 2000 and/or 2001 226 km South African Ironman Triathlons and 143 Caucasian controls for the ACTN3 R577X mutation. They found no significant differences in either the genotype (p = 0.486) or allele (p = 0.375) frequencies within the fastest, middle of the field, or slowest Caucasian male finishers and the control population.
In 52 white and 23 black elite-level bodybuilders and powerlifters from the U.S., Roth et al. (2008) found significantly lower XX genotype frequency in strength athletes (6.7%) compared to controls (16.3%; p = 0.005). The XX genotype was significantly lower in white athletes (9.7%) compared to white controls (19.9%; p = 0.018), but did not reach significance in black athletes (0%) compared to black controls (4.8%; p = 0.10). Roth et al. (2008) concluded that the 577X allele is underrepresented in elite strength athletes in addition to sprint athletes, consistent with previous reports indicating that ACTN3 deficiency appears to impair muscle performance.
