Actn3 Deficiency
A number sign (#) is used with this entry because ACTN3 deficiency is caused by a homozygous nonsense polymorphism in the ACTN3 gene (102574) on chromosome 11q13.
DescriptionApproximately 16% of the world population is predicted to have congenital deficiency of alpha-actinin-3 based on a common nonsense polymorphism in the ACTN3 gene. Expression of alpha-actinin-3 is limited to a subset of type 2 (fast) fibers. No disease phenotype is associated with this deficiency (North et al., 1999).
Clinical FeaturesAlthough ACTN3 deficiency is not associated with a disease phenotype, there are some reports that ACTN3 genotype is associated with athletic performance, including sprinting and endurance; see MOLECULAR GENETICS.
Molecular GeneticsACTN3 Deficiency
North et al. (1999) identified a common nonsense mutation in ACTN3, arg577-to-ter (R577X; 102574.0001; rs1815739), in the general population in many ethnic groups. The R577X mutation had an allele frequency ranging from 0.22 +/- 0.05 to 0.52 +/- 0.04 in ethnic populations from Asia, the Americas, Australasia, Africa, and Europe. Approximately 16% of the world population is predicted to have congenital deficiency of alpha-actinin-3. No disease phenotype is associated with this deficiency. North et al. (1999) concluded that other factors likely compensate for the absence of alpha-actinin-3 at the Z lines of skeletal muscle fast fibers. These results demonstrated that ACTN3 is not an essential gene, and suggested that absence of a structural protein caused by homozygosity for a null mutation cannot be assumed to be disease-related without additional family and population data.
Sprinting Performance
Yang et al. (2003) demonstrated highly significant associations between ACTN3 genotype and athletic performance. Both male and female elite sprint athletes had significantly higher frequencies of the 577R allele than did controls. This suggested that the presence of alpha-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity, and provides an evolutionary advantage because of increased sprint performance. There is also a genotype effect in female sprint and endurance athletes, with higher than expected numbers 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. It is likely that there is a 'trade off' between sprint and endurance traits that imposes important constraints on the evolution of physical performance in humans and other vertebrates (Garland et al., 1990). This hypothesis is supported by data from world-class decathletes, which demonstrated that performance in the 100-meter sprint, shot put, long jump, and 110-meter hurdles (which rely on explosive power and fast fatigue-susceptible muscle fibers) is negatively correlated with performance in the 1,500-meter race (which requires endurance and fatigue-resistant slow fiber activity) (Van Damme et al., 2002).
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.