Jean K. Mah, Doug Biggar
Duchenne muscular dystrophy (DMD, OMIM #310200) is the most common form of muscular dystrophy in childhood, with an incidence of approximately 1 per 3,500 live-born males. It is caused by mutations of the DMD gene located on Xp21 which codes for dystrophin, a 427-kDa protein that is expressed at the sarcolemma of skeletal muscle. The dystrophin gene contains 79 exons, which includes an actin-binding domain at the N-terminus, 24 spectrin-like repeat units, a cysteine-rich dystroglycan binding site, and a C-terminal domain. The large size of the dystrophin gene results in a complex mutational spectrum (>4,700 different mutations) as well as a high spontaneous mutation rate. Large deletions account for approximately 65% of DMD mutations while duplications occur in up to 10% of males with DMD. The remaining 25% include small deletions, insertions, point mutations, or splicing mutations. About two-thirds of DMD cases are inherited from mothers carrying the mutations, with the remaining one-third occurring as spontaneous mutations. According to Monaco et al, DMD-causing mutations are typically associated with an out-offrame mutation leading to a loss of functional gene product, whereas in-frame mutations that allow synthesis of an internally truncated but functional protein result in a milder Becker muscular dystrophy (BMD) phenotype.
University of Calgary, Canada; University of Toronto, Canada