25463232

25463232 - Traffic 2007; 8: 785794 Blackwell Munksgaard #...

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# 2007 The Authors Journal compilation # 2007 Blackwell Publishing Ltd doi: 10.1111/j.1600-0854.2007.00573.x Traffic 2007; 8: 785–794 Blackwell Munksgaard Review Dysferlin in Membrane Trafficking and Patch Repair Louise Glover and Robert H. Brown Jr* Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA *Corresponding author: Robert H. Brown Jr, rhbrown@partners.org The muscular dystrophies are a heterogeneous group of inherited disorders, defined by progressive muscle weak- ness and atrophy. Following the discovery of dystrophin, remarkable progress has been made in defining the molecular properties of proteins involved in the various dystrophies. This has underlined the importance of the dystrophin-associated protein complex as a cell mem- brane scaffold, providing structural stability to muscle cells (McNeil PL, Khakee R. Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. Am J Pathol 1992;140:1097–1109). While the dystrophies linked to loss of function of dystrophin and its associated proteins are caused by diminished membrane integrity, it is now believed that a new class of dystrophies arises because of a diminished capacity for rapid muscle mem- brane repair after injury. Dysferlin is the first identified member of a putative muscle-specific repair complex that permits rapid resealing of membranes disrupted by mechanical stress. Membrane resealing is a function conserved by most cells and is mediated by a mechanism closely resembling regulated, Ca 2 1 -dependent exocyto- sis. A primary role for dysferlin in this pathway, as a Ca 2 1 - regulated fusogen, has been suggested, and a number of candidate partner proteins have been identified. This review outlines the current understanding of the role of dysferlin in membrane repair and the evolving picture of dysferlin-related signaling pathways in muscle cell phys- iology and pathology. Key words: C2 domain, Ca 2 1 -regulated exocytosis, mem- brane fusion, membrane repair, muscular dystrophy Received 5 March 2007, revised and accepted for publica- tion 26 March 2007, uncorrected manuscript published online 29 March 2007 Dysferlin and the Muscular Dystrophies Muscular dystrophies (MDs) are a diverse group of myo- genic disorders, characterized by progressive loss of muscle strength and integrity. Clinical features can present at any age from birth to midlife, often including high serum levels of the muscle-specific enzyme creatine kinase (CK), and vary widely in rate of disease progression (1). To date, more than 30 gene loci have been identified harboring mutations that cause MD, emphasizing the molecular diversity underlying these disorders. The limb–girdle mus- cular dystrophy (LGMD) phenotype is defined by weak- ness and wasting predominantly in the pelvic and shoulder muscles, with onset generally in the second or third decade of life and with relatively slow progression. Even within the LGMD classification, there exists considerable
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This note was uploaded on 10/12/2010 for the course BC BC367 taught by Professor Millard during the Spring '10 term at Colby.

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25463232 - Traffic 2007; 8: 785794 Blackwell Munksgaard #...

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