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

Mills, Michelle A.; Nan Yang; P. Weinberger, Ron; Woude, Douglas L. Vander; Beggs, Alan H.; Easteal, Simon; North, Kathryn N.
June 2001
Human Molecular Genetics;Jun2001, Vol. 10 Issue 13, p1335
Academic Journal
The α-actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of α-actinin (ACTN2 and ACTN3) are major structural components of the Z-line involved in anchoring 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 α-actinin-3 is absent in ∼18% of individuals in a range of human populations, and that homozygosity for a premature stop codon (577X) accounts for most cases of true α-actinin-3 deficiency. Absence of α-actinin-3 is not associated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that α-actinin-2 is able to compensate for α-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 mouse genome contains four orthologues which all map to evolutionarily conserved syntenic regions for the four human genes. Murine Actn2 and Actn3 are differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, α-actinin-2 expression does not completely overlap α-actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken α-actinin genes demonstrates that ACTN3 has been conserved over a long period of evolutionary time, implying a constraint on evolutionary rate imposed by continued function of the gene. These observations provide a real framework in which to test theoretical models of genetic redundancy as they apply 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.


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