Molecular genetic analysis of dysferlin in Japanese patients with Miyoshi myopathy

Miyoshi myopathy (MM) is an autosomal recessive distal muscular dystrophy first described by Miyoshi in 1967. MM is caused by mutations of a dysferlin gene (DYSF) at chromosome 2p13. We identified 8 novel mutations and 3 polymorphisms in the DYSF among seven unrelated Japanese families. The mutations in our MM occurred throughout the DYSF and showed no mutational hot spot. Expression of dysferlin at the plasma membrane of skeletal muscle was deficient in all the patients studied. In two families, we found two distinct clinical phenotypes (distal and proximal dominancies) within a family. This is the first report of DYSF mutations and dysferlin deficiency in Japanese patients with MM. Our findings suggest, (1) the specific deficiency of dysferlin at the plasma membrane of skeletal muscle in MM, (2) the ethnic difference in DYSF mutations and (3) the presence of possible genetic or environmental modification factors which influence the clinical variability of MM.