Myoferlin, a candidate gene and potential modifier of muscular dystrophy

Dysferlin, the gene product of the limb girdle muscular dystrophy (LGMD) 2B locus, encodes a membrane-associated protein with homology to Caenorhabdit is elegans fer-l, Humans with mutations in dysferlin (DYSF) develop muscle weakness that affects both proximal and distal muscles, Strikingly, the phe notype in LGMD 2B patients is highly variable, but the type of mutation in DYSF cannot explain this phenotypic variability. Through electronic databas e searching, we identified a protein highly homologous to dysferlin that we have named myoferlin, Myoferlin mRNA was highly expressed in cardiac muscl e and to a lesser degree in skeletal muscle. However, antibodies raised to myoferlin showed abundant expression of myoferlin in both cardiac and skele tal muscle, Within the cell, myoferlin was associated with the plasma membr ane but, unlike dysferlin, myoferlin was also associated with the nuclear m embrane. Ferlin family members contain C2 domains, and these domains play a role in calcium-mediated membrane fusion events. To investigate this, we s tudied the expression of myoferlin in the mdx mouse, which lacks dystrophin and whose muscles undergo repeated rounds of degeneration and regeneration . We found upregulation of myoferlin at the membrane in mdx skeletal muscle , Thus, myoferlin (MYOF) is a candidate gene for muscular dystrophy and car diomyopathy, or possibly a modifier of the muscular dystrophy phenotype.