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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01172

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Myopathy mutations in -skeletal-muscle actin cause a range of molecular defects

Céline F. Costa^1,*, Heidi Rommelaere², Davy Waterschoot², Kamaljit K. Sethi¹, Kristen J. Nowak^3,4,, Nigel G. Laing^3,4, Christophe Ampe² and Laura M. Machesky^1,

¹ School of Biosciences, Division of Molecular Cell Biology, University of Birmingham, Birmingham B15 2TT, UK
² Department of Biochemistry, Ghent University and Flanders Interuniversity Institute for Biotechnology (VIB09), B-9052 Gent, Belgium
³ Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, Nedlands
⁴ Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia

Author for correspondence (e-mail: l.m.machesky{at}bham.ac.uk)

Accepted 23 February 2004

Mutations in the gene encoding -skeletal-muscle actin, ACTA1, cause congenital myopathies of various phenotypes that have been studied since their discovery in 1999. Although much is now known about the clinical aspects of myopathies resulting from over 60 different ACTA1 mutations, we have very little evidence for how mutations alter the behavior of the actin protein and thus lead to disease. We used a combination of biochemical and cell biological analysis to classify 19 myopathy mutants and found a range of defects in the actin. Using in vitro expression systems, we probed actin folding and actin's capacity to interact with actin-binding proteins and polymerization. Only two mutants failed to fold; these represent recessive alleles, causing severe myopathy, indicating that patients produce nonfunctional actin. Four other mutants bound tightly to cyclase-associated protein, indicating a possible instability in the nucleotide-binding pocket, and formed rods and aggregates in cells. Eleven mutants showed defects in the ability to co-polymerize with wild-type actin. Some of these could incorporate into normal actin structures in NIH 3T3 fibroblasts, but two of the three tested also formed aggregates. Four mutants showed no defect in vitro but two of these formed aggregates in cells, indicating functional defects that we have not yet tested for. Overall, we found a range of defects and behaviors of the mutants in vitro and in cultured cells, paralleling the complexity of actin-based muscle myopathy phenotypes.

Key words: Actin, Nemaline myopathy, Actin polymerization, Protein folding, Myopathy, Actin mutations

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