@article{5a8c2bbd7415471f9d42e1ec24b54518,
title = "Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy",
abstract = "Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle α-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.",
author = "Nowak, {Kristen J.} and Duangrurdee Wattanasirichaigoon and Goebel, {Hans H.} and Matthew Wilce and Katarina Pelin and Kati Donner and Jacob, {Rebecca L.} and Christoph H{\"u}bner and Konrad Oexle and Anderson, {Janice R.} and Verity, {Christopher M.} and North, {Kathryn N.} and Iannaccone, {Susan T.} and M{\"u}ller, {Clemens R.} and Peter N{\"u}rnberg and Francesco Muntoni and Caroline Sewry and Imelda Hughes and Rebecca Sutphen and Lacson, {Atilano G.} and Swoboda, {Kathryn J.} and Jaqueline Vigneron and Carina Wallgren-Pettersson and Beggs, {Alan H.} and Laing, {Nigel G.}",
note = "Funding Information: We thank the patients and their families for samples; members of the European Neuromuscular Centre International Consortium on Nemaline Myopathy for collaboration; and C. Huxtable and F. Mastaglia for critical reading of the manuscript. This work was funded by the Australian National Health and Medical Research Council and the Neuromuscular Foundation of Western Australia (K.N., R.L.J., N.G.L.), the Muscular Dystrophy Association and the National Institutes of Health (D.W., A.H.B.), the Deutsche Gesellschaft f{\"u}r Muskelkranke e. V. Freiburg/Germany (H.H.G.), the Association Fran{\c c}aise contre les Myopathies, the Swedish Cultural Foundation of Finland, the Finska L{\"a}kares{\"a}llskapet and the Medicinska underst{\"o}dsf{\"o}reningen Liv och H{\"a}lsa (K.P., K.D., C.W.P). We also thank the European Neuromuscular Centre (ENMC) and its main sponsors: Association Francaise contre les Myopathies, Italian Telethon Committee, Muscular Dystrophy Group of Great Britain and Northern Ireland, Vereniging Spierziekten Nederland and Deutsche Gesellschaft f{\"u}r Muskelkranke, Schweizerische Stiftung f{\"u}r die Erforschung der Muskelkrankheiten, Prinses Beatrix Fonds, Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria) and Muskelsvindfonden (Denmark); and associate members Unione Italiana Lotta alla Distrofia Muscolare and Muscular Dystrophy Association of Finland.",
year = "1999",
month = oct,
doi = "10.1038/13837",
language = "English (US)",
volume = "23",
pages = "208--212",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",
}