The structural and functional diversity of dystrophin

Abstract

Duchenne and Becker muscular dystrophies are caused by defects of the dystrophin gene. Expression of this large X-linked gene is under elaborate transcriptional and splicing control. At least five independent promoters specify the transcription of their respective alternative first exons in a cell-specific and developmentally controlled manner. Three promoters express full-length dystrophin, while two promoters near the C terminus express the last domains in a mutually exclusive manner. Six exons of the C terminus are alternatively spliced, giving rise to several alternative forms. Genetic, biochemical and anatomical studies of dystrophin suggest that a number of distinct functions are subserved by its great structural diversity. Extensive studies of dystrophin may lead to an understanding of the cause and perhaps a rational treatment for muscular dystrophy.

Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center

“…It consists of 79 exons, forming a 14-kb mRNA transcript, and lengthy introns (up to 250 kb). 2 Mutation studies on the dystrophin gene have focused on detecting deletions or duplications of one or more exons, and multiplex PCR that amplifies selected deletion-prone exons has been used as the most efficient method of mutation detection. 3,4 In these gross rearrangements, the reading frame rule explains the clinical difference between DMD and BMD at the molecular level; that is, deletions or duplications that shift the reading frame of the dystrophin mRNA (out-of-frame) lead to the more severe DMD phenotype, whereas the milder BMD phenotype occurs if the reading frame is preserved (in-frame).…”

Proteomic profiling of naturally protected extraocular muscles from the dystrophin-deficient mdx mouse

“…Dystrophinopathies are characterized by a primary deficiency in the Dp427 isoform of the membrane cytoskeletal protein dystrophin [1] and secondary abnormalities in sarcolemmal stability, ion homeostasis, cellular signaling, excitation-contraction coupling, and numerous metabolic pathways [2]. Severely progressive Duchenne muscular dystrophy (DMD) and the more benign Becker muscular dystrophy are allelic muscle diseases and are classified according to changes in the expression level and/or size of dystrophin [3].…”

Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

“…Dystrophin is the major cytoskeletal component of a large, transmembrane complex (Ahn and Kunkel, 1993;Matsumura and Campbell, 1994;Ozawa et al, 1998) that plays a role in signaling from the plasma membrane of skeletal myofibers (sarcolemma) to the cytoplasm (Rando, 2001;Lapidos et al, 2004) and in transmitting the force of contraction across the sarcolemma to extracellular structures (Campbell, 1995;Bloch and Gonzalez-Serratos, 2003). Here, we focus on the latter role, and particularly, on the nature of the connections made between the contractile apparatus and the sarcolemma, at sites termed "costameres" (Bloch and Gonzalez-Serratos, 2003;Ervasti, 2003).…”