Mutations in the nebulin gene associated with autosomal recessive nemalinemyopathy

The congenital nemaline myopathies are rare hereditary muscle disorders cha racterized by the presence in the muscle fibers of nemaline bodies consisti ng of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, th e disease is caused by a mutation in the a-tropomyosin gene TPM3. The typic al form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are ass ociated with the disease. The nebulin protein is a giant protein found in t he thin filaments of striated muscle. A variety of nebulin isoforms are tho ught to contribute to the molecular diversity of Z discs. We have studied t he 3' end of the 20.8-kb cDNA encoding the Z disc part of the 800-kDa prote in and describe six disease-associated mutations in patients from five fami lies of different ethnic origins. In two families with consanguineous paren ts, the patients were homozygous for point mutations. In one family with no nconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immu nofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to dise ase pathogenesis.