Abstract for presentation at 11th International Congress of Human Genetics

A gene for speed: The ACTN3 R577X polymorphism influences muscle performance

  • Daniel MacArthur, Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, Australia, Australia
  • Dr Nan Yang, Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, Australia, Australia
  • Ms Jane Seto, Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, Australia, Australia
  • Ms Joanna Raftery, Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, Australia, Australia
  • Dr Anthony Kee, Muscle Development Unit, Children's Medical Research Institute, Sydney, Australia, Australia
  • Dr Edna Hardeman, Muscle Development Unit, Children's Medical Research Institute, Sydney, Australia, Australia
  • Dr Peter Gunning, Oncology Research Unit, Children's Hospital at Westmead, Sydney, Australia, Australia
  • Dr Kathryn North, Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, Australia, Australia

    • The protein α-actinin-3, encoded by the ACTN3 gene, is a highly conserved component of the contractile machinery in fast skeletal muscle fibres. Intriguingly, a common nonsense variant in the human ACTN3 gene (R577X) results in complete deficiency of α-actinin-3 in ~18% of the general population who are homozygous for the X allele - more than one billion individuals worldwide. We have recently demonstrated a significantly lower frequency of XX homozygotes amongst elite Australian sprint athletes than controls, suggesting that the presence of α-actinin-3 is required for optimal fast fibre function. This finding has been supported by a number of recent studies demonstrating associations between R577X genotype and muscle function. The ACTN3 R577X polymorphism thus represents a common genetic factor influencing muscle performance in humans.
    We have developed an ACTN3 knockout mouse model that replicates human α-actinin-3 deficiency. We have demonstrated that the closely related protein, α-actinin-2, is able to compensate for the absence of α-actinin-3 in sarcomere assembly and function at baseline physiological conditions. Loss of α-actinin-3 results in the upregulation of several proteins associated with the muscle disease myofibrillar myopathy, which involves a loss of Z line integrity. Our knockout mouse demonstrates that α-actinin-3 deficiency results in increased sarcomeric damage caused by eccentric muscle contraction. In combination these data suggest that α-actinin-3 plays an important role in maintaining the mechanical integrity of the muscle sarcomere during contractions associated with power and sprint activities.
    We are also investigating the evolutionary history of the 577X allele in humans by analysing genetic variation in the R577X region in different ethnic groups. Our preliminary data suggest that balancing selection acts at the R577X locus. Based on our athlete data, we hypothesise that this balancing selection may arise from an evolutionary trade-off between the power and endurance advantages provided by the R and X alleles, respectively. Our studies of the mouse model of α-actinin-3 provide insight into the mechanistic basis of these advantages.

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