Differential expression of the actin-binding proteins, alpha-actinin-2 and-3, in different species: implications for the evolution of functional redundancy

The alpha -actinins are a multigene family of four actin-binding proteins r elated to dystrophin. The two skeletal muscle isoforms of alpha -actinin (A CTN2 and ACTN3) are major structural components of the Z-line involved in a nchoring the actin-containing thin filaments. In humans, ACTN2 is expressed in all muscle fibres, while ACTN3 expression is restricted to a subset of type 2 fibres. We have recently demonstrated that alpha -actinin-3 is absen t in similar to 18% of individuals in a range of human populations, and tha t homozygosity for a premature stop codon (577X) accounts for most cases of true alpha -actinin-3 deficiency. Absence of alpha -actinin-3 is not assoc iated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that alpha -actinin-2 is able to compensate for alpha -actinin-3 deficiency. We now present data concerning the expression of ACTN3 in other species. Genotyping of non-human primates indicates that the 577X null mutation has likely arisen in humans. The mous e genome contains four orthologues which all map to evolutionarily conserve d syntenic regions for the four human genes. Murine Actn2 and Actn3 are dif ferentially expressed, spatially and temporally, during embryonic developme nt and, in contrast to humans, alpha -actinin-2 expression does not complet ely overlap alpha -actinin-3 in postnatal skeletal muscle, suggesting indep endent function. Furthermore, sequence comparison of human, mouse and chick en a-actinin genes demonstrates that ACTN3 has been conserved over a long p eriod of evolutionary time, implying a constraint on evolutionary rate impo sed by continued function of the gene. These observations provide a real fr amework in which to test theoretical models of genetic redundancy as they a pply to human populations. In addition we highlight the need for caution in making conclusions about gene function from the phenotypic consequences of loss-of-function mutations in animal knockout models.