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.