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Human Molecular Genetics, 1999, Vol. 8, No. 7 1329-1336
© 1999 Oxford University Press

Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy

Paula Salmikangas, Olli-Matti Mykkänen, Mikaela Grönholm, Leena Heiska, Juha Kere1 and Olli Carpéna

Departments of Pathology and 1Medical Genetics, University of Helsinki, Haartman Institute, Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland

The striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin, a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and {alpha}-actinin, an actin cross-linking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy. On the other hand, the disease genes underlying several disease forms remain to be identified. Here we describe a novel 57 kDa cytoskeletal protein, myotilin. Its N-terminal sequence is unique, but the C-terminal half contains two Ig-like domains homologous to titin. Myotilin is expressed in skeletal and cardiac muscle, it co-localizes with {alpha}-actinin in the sarcomeric I­-bands and directly interacts with {alpha}-actinin. The human myotilin gene maps to chromosome 5q31 between markers AFM350yB1 and D5S500. The locus of a dominantly inherited limb-girdle muscular dystrophy (LGMD1A) resides in an overlapping narrow segment, and a new type of distal myopathy with vocal cord and pharyngeal weakness (VCPMD) has been mapped to the same locus. The muscle specificity and apparent role as a sarcomeric structural protein raise the possibility that defects in the myotilin gene may cause muscular dystrophy.

a To whom correspondence should be addressed. Tel: +358 9 1912 6413; Fax: +358 9 1912 6700; Email: olli.carpen{at}helsinki.fi

DDBJ/EMBL/GenBank accession no. AF144477.


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