ABSTRACT
Duchenne muscular dystrophy (DMD) is the most prevalent and severe form of human muscular dystrophy. While clinical descriptions of DMD date back to the 1850s, over 100 years passed before evidence suggested that the muscle cell plasma mem brane, or sarcolemma, is compromised in DMD muscle. The molecular basis for DMD and its associated sarcolemmal instability became more clear with landmark studies published in the mid-to-late 1980s which identified the gene defective in DMD.1 The DMD locus spans over 2.5 million bases distinguishing it as the largest gene in the human genome. The array of transcripts expressed from the DMD gene is complex due to the presence of multiple promot ers and alternative splicing. The largest transcripts encode a four-domain protein with a pre dicted molecular weight of427,000, named dystrophin. Dystrophin is the predominant DMD transcript expressed in striated muscle and DMD gene mutations, deletions or duplications most frequendy result in a loss of dystrophin expression in muscle of patients afflicted with DMD. Based on its localization to the cytoplasmic face of the sarcolemma and sequence simi larity with domains/moufs common to proteins of the actin-based cytoskeleton, dystrophin was hypothesized early on to play a structural role in anchoring the sarcolemma to the under lying cytoskeleton and protect the sarcolemma against stress imposed during muscle contrac tion or stretch. Biochemical studies aimed at confirming the hypothesized structure and func tion of dystrophin revealed its tight association with a multi-subunit complex, the so-named dystrophin-glycoprotein complex. Since its description, the dystrophin-glycoprotein complex has emerged as an important structural unit of muscle and also as a critical nexus for under standing muscular dystrophies arising from defects in several distinct genes.
