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J. Biol. Chem., Vol. 278, Issue 50, 50466-50473, December 12, 2003

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Dysferlin Interacts with Annexins A1 and A2 and Mediates Sarcolemmal Wound-healing^*

Niall J. Lennon, Alvin Kho, Brian J. Bacskai¶, Sarah L. Perlmutter, Bradley T. Hyman¶, and Robert H. Brown, Jr.||

From the Day Neuromuscular Research Laboratory and ^¶Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129 and Children's Hospital Informatics Program, Boston, Massachusetts 02115

Mutations in the dysferlin gene cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy. We report here the results of expression profile analyses and in vitro investigations that point to an interaction between dysferlin and the Ca²⁺ and lipid-binding proteins, annexins A1 and A2, and define a role for dysferlin in Ca²⁺-dependent repair of sarcolemmal injury through a process of vesicle fusion. Expression profiling identified a network of genes that are co-regulated in dysferlinopathic mice. Co-immunofluorescence, co-immunoprecipitation, and fluorescence lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and A2 in a Ca²⁺ and membrane injury-dependent manner. The distribution of the annexins and the efficiency of sarcolemmal wound-healing are significantly disrupted in dysferlin-deficient muscle. We propose a model of muscle membrane healing mediated by dysferlin that is relevant to both normal and dystrophic muscle and defines the annexins as potential muscular dystrophy genes.

Received for publication, July 7, 2003 , and in revised form, September 2, 2003.

^* Funding for these studies was generously provided by NINDS Grant 5PO1NS40828–02 from the National Institutes of Health, the Cecil B. Day Investment Company, and the Muscular Dystrophy Association (to R. H. B. and N. J. L.), National Institutes of Health Grant AG08487, a Pioneer Award from the Alzheimer's Association, the Walter's Family Foundation (to B. T. H.), and National Institutes of Health Grants EB00768 and AG020570 (to B. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains the gene expression table.

^|| To whom correspondence should be addressed: Day Neuromuscular Research Laboratory, MGH-East, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-5750; Fax: 617-726-8543; E-mail: rhbrown{at}partners.org.

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