Human Molecular Genetics, 2000, Vol. 9, No. 14 2141-2147
© 2000 Oxford University Press
Myotilin is mutated in limb girdle muscular dystrophy 1A
Department of Medicine, Section of Medical Genetics, Duke University Medical Center, DUMC 3445, Durham, NC 27710-3445, USA, 1University of Illinois at Chicago, Chicago, IL, USA, 2University of Helsinki, Helsinki, Finland and 3Rhode Island Hospital, Providence, RI, USA
We have identified a mutation in the myotilin gene in a large North American family of German descent expressing an autosomal dominant form of limb girdle muscular dystrophy (LGMD1A). We have previously mapped this gene to 5q31. Symptoms of this adult onset disease are progressive weakness of the hip and shoulder girdles, as well as a distinctive dysarthric pattern of speech. Muscle of affected individuals shows degeneration of myofibers, variations in fiber size, fiber splitting, centrally located myonuclei and a large number of autophagic vesicles. Affected muscle also exhibits disorganization and streaming of the Z-line similar to that seen in nemaline myopathy. We have identified a C450T missense mutation in the myotilin gene that is predicted to result in the conversion of residue 57 from threonine to isoleucine. This mutation has not been found in 396 control chromosomes. The mutant allele is transcribed and normal levels of correctly localized myotilin protein are seen in LGMD1A muscle. Myotilin is a sarcomeric protein that binds to 
-actinin and is localized in the Z-line. The observed missense mutation does not disrupt binding to -actinin.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +1 919 684 3508; Fax: +1 919 684 2275; Email: mhauser@chg.mc.duke.edu
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