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Human Molecular Genetics, 2001, Vol. 10, No. 13 1335-1346
© 2001 Oxford University Press

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

Michelle Mills1, Nan Yang1, Ron Weinberger3, Douglas L. Vander Woude4, Alan H. Beggs4, Simon Easteal5 and Kathryn North1,2,+

1Neurogenetics Research Unit, Children’s Hospital at Westmead, Sydney, NSW, Australia, 2Department of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia, 3Oncology Research Unit, Children’s Hospital at Westmead, Sydney, NSW, Australia, 4Genetics Division, Children’s Hospital, Harvard Medical School, Boston, MA, USA and 5Centre for Bioinformation Science, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

The {alpha}-actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of {alpha}-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 {alpha}-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 {alpha}-actinin-3 deficiency. Absence of {alpha}-actinin-3 is not associated 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 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, {alpha}-actinin-2 expression does not completely overlap {alpha}-actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken {alpha}-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.

+ To whom correspondence should be addressed at: Clinical Sciences Building, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia; Tel: +61 2 9845 3011; Fax: +61 2 9845 3082; Email: kathryn@chw.edu.auThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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