Human Molecular Genetics Advance Access originally published online on March 11, 2008
Human Molecular Genetics 2008 17(12):1855-1866; doi:10.1093/hmg/ddn081
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Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle
1 Center for Human and Clinical Genetics 2 Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands 3 Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK
* To whom correspondence should be addressed at: Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Tel: +3171 5269480; Fax: +31 71526 8285; Email: maarel{at}lumc.nl
Received January 17, 2008; Accepted March 9, 2008
Muscular dystrophies comprise a genetically heterogeneous group of degenerative muscle disorders characterized 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 findings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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