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Calpain-3 dysferlin protein complex

Calpain-3 dysferlin protein complex - Human Molecular...

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Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle Yanchao Huang 1, { , Antoine de Morre ´e 1, { , Alexandra van Remoortere 2 , Kate Bushby 3 , Rune R. Frants 1 , Johan Tden Dunnen 1 and Silve `re M. van der Maarel 1, ± 1 Center for Human and Clinical Genetics and 2 Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands and 3 Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK Received January 17, 2008; Revised and Accepted March 9, 2008 Muscular dystrophies comprise a genetically heterogeneous group of degenerative muscle disorders charac- terized by progressive muscle wasting and weakness. Two forms of limb-girdle muscular dystrophy, 2A and 2B, are caused by mutations in calpain 3 (CAPN3) and dysferlin (DYSF), respectively. While CAPN3 may be involved in sarcomere remodeling, DYSF is proposed to play a role in membrane repair. The coexistence of CAPN3 and AHNAK, a protein involved in subsarcolemmal cytoarchitecture and membrane repair, in the dysferlin protein complex and the presence of proteolytic cleavage fragments of AHNAK in skeletal muscle led us to investigate whether AHNAK can act as substrate for CAPN3. We here demonstrate that AHNAK is cleaved by CAPN3 and show that AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients. Moreover, we demonstrate that AHNAK fragments cleaved by CAPN3 have lost their affinity for dysferlin. Thus, our find- ings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex. INTRODUCTION Muscular dystrophies comprise a heterogeneous group of inherited degenerative muscle disorders characterized by pro- gressive muscle wasting and weakness with variable distri- bution and severity. Since the discovery of dystrophin, a large number of genes either associated with, or linked to, various forms of muscular dystrophy (MD) have been ident- ified. Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of primary myopathies showing progressive weakness and wasting of the muscles of the pelvic and shoulder girdle, and ranging from severe forms with onset in the first decade with rapid progression to milder forms with later onset and a slower course. Three different major disease mechanisms are emerging for LGMD: a structural defect in the muscle membrane, muscle membrane repair deficiency and defects in sarcomere remodel- ing, cytoskeleton structure and cytoskeleton-membrane interactions. Limb-girdle muscular dystrophy type 2A (LGMD2A; OMIM# 253600) or calpainopathy is considered the most frequent form of recessive LGMD world wide (1–3). The gene responsible for LGMD2A and coding for calpain 3 (CAPN3; OMIM# 114240) was localized by linkage analysis to the chromosomal region 15q15.1–15.3 and subsequently identified by positional cloning (3). To date well over 350 dis- tinct pathogenic mutations in the calpain 3 gene have been
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