Studies on muscular dystrophy associated genes
Muscular dystrophy is a collective group of genetic disorder that results in progressive wasting of skeletal muscle. Dysferlin, the gene responsible for Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi Myopathy (MM) was found to be a member of a newly identified protein family named the ferlins. Recent work has suggested that dysferlin is necessary for efficient calcium sensitive membrane resealing therefore is involved in membrane repair, a mechanism which if defective results in progressive muscle wasting. In this project, the involvement of other genes that could possibly be associated with muscular dystrophy is investigated. Myoferlin, a member of the ferlin protein family is highly homologous to dysferlin and is also a plasma membrane protein with six C2 domains and a C-terminus transmembrane domain. To date no disease has been associated with mutations in the myoferlin gene but its high similarity to dysferlin means that it could be a potential muscular dystrophy associated gene. Results obtained from this study strongly suggest that myoferlin like dysferlin is enriched at plasma membrane disruption sites and during myoblast differentiation, two processes which involve the fusion of two opposed bilayers, a process vital in membrane repair. In addition, a fifth member of the ferlin protein family is reported in this project and the primary results obtained are consistent with it being a potential muscular dystrophy associated gene. Finally, a group of MM affected families that were previously excluded for mutations in their dysferlin gene were analysed for muscular dystrophy associated genes other than dysferlin.