ACTN3 Mutation

ACTN3 Gene

• The ACTN3 Gene is located on Chromosome 11 and codes for the 'alpha-actinin-3' protein

• Alpha-actinin-3 is a 'sarcomeric' protein expressed only in type 2 fibres or "fast twitch fibers"

• These sarcomeric alpha-actinins are fundamental components of the Z line (boundary between sarcomeres) interacting with ‘actin,’ a protein that produces muscle, and are necessary for producing explosive muscular contractions.

• alpha-actinine affects these skeletal-muscles by anchoring actin filaments to the Z-line, necessary for stress fiber formation and stability, as well as producing athletic power and speed by triggering the production capacity of strong muscle fibers, commonly prevalent in sprinters and powerlifters.

Point Mutation

ACTN3 Gene

Mutation

Allelic Variants

Survival Advantage

• In the ACTN3 gene, a point mutation in the form of a base substitution occurs (C to T) during translation, where RNA is converted into an amino acid chain during protein synthesis and the mutation results in functional changes in the synthesised protein.

• This base substitution results in the transformation of the ‘arginine’ (R) amino acid into a premature stop codon, resulting in polymorphisms of the gene as the normal 577R allele and the mutated 577X allele.

• Individuals with the X allele are alpha-actinine-3 deficient, due to the premature stop codon resulting in a shorter and non-functional version of alpha-actinine, further classifying it as a nonsense mutation.

• Individuals with the homozygous XX allele express a non-functional alpha-actinine-3 protein while individuals with the homozygous RR allele and heterozygous Rx allele express a functional alpha-actinine-3 protein.

R-allele

X-allele

• Reduced athletic ability

• Reduced response to resistance training

• Increased post-exercise muscle damage following intense training

• Increased injury risk, however possibly enhanced flexibility

• Explosive power athletes, able to exert maximum force over a short period of time

• Enhanced response to resistance training

• Reduced post-exercise muscle damage following intense training

• Reduced injury risk, however possible reduction in flexibility

• Even though the X-allele is highly ineffectual, it provides 1.5 billion people around the world with a major survival advantage and has been part of the human genome for 1 million years.

• The prevalence of the 577X allele increased as humans migrated out of Africa and inhabited colder climates of central and northern Europe, suggesting a link between alpha-actinin-3 deficiency and improved tolerance for cold

• XX allele individuals are better at regulating their core body temperatures during cold exposure due to changes in their ‘skeletal muscle thermogenesis’, where they shift towards non-shivering thermogenesis and keep their body temperature controlled through an increase in metabolic heat production.

• The heat produced from shivering is effective at counteracting the heat loss from cold exposure, but shivering is metabolically inefficient and uncomfortable. Ideally, nonshivering thermogenesis is the most effective way to adapt to a cold environment.

• Furthermore, A study conducted by the NCBI in 2021 found associations between rate of temperature decline and time in both RR and XX polymorphisms, where XX individuals had a much slower rate of temperature decline in cold conditions.