TY - JOUR
T1 - Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy
AU - Nowak, Kristen J.
AU - Wattanasirichaigoon, Duangrurdee
AU - Goebel, Hans H.
AU - Wilce, Matthew
AU - Pelin, Katarina
AU - Donner, Kati
AU - Jacob, Rebecca L.
AU - Hübner, Christoph
AU - Oexle, Konrad
AU - Anderson, Janice R.
AU - Verity, Christopher M.
AU - North, Kathryn N.
AU - Iannaccone, Susan T.
AU - Müller, Clemens R.
AU - Nürnberg, Peter
AU - Muntoni, Francesco
AU - Sewry, Caroline
AU - Hughes, Imelda
AU - Sutphen, Rebecca
AU - Lacson, Atilano G.
AU - Swoboda, Kathryn J.
AU - Vigneron, Jaqueline
AU - Wallgren-Pettersson, Carina
AU - Beggs, Alan H.
AU - Laing, Nigel G.
PY - 1999/10/1
Y1 - 1999/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032858915&partnerID=8YFLogxK
U2 - 10.1038/13837
DO - 10.1038/13837
M3 - Article
C2 - 10508519
AN - SCOPUS:0032858915
VL - 23
SP - 208
EP - 212
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 2
ER -