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Thesis Antoine de Morree: Limb Girdle Muscular Dystrophy
07 February 2011

Titel thesis: Functional Protein Networks Unifying Limb Girdle Muscular Dystrophy
Author: Antoine de Morree

Summary
Limb Girdle Muscular Dystrophy (LGMD) is a rare heterogeneous disorder that can be caused by mutations in at least 21 different genes. These genes are often widely expressed and encode proteins with highly diverse functions. And yet mutations in all of them give rise to a similar clinical presentation: adult onset muscle weakness, with muscles of the pelvic and shoulder girdle as predominantly affected muscle groups. In my thesis I explored a potential molecular mechanism that unifies the different genetic defects, which individually can cause a limb girdle muscular dystrophy.

We started with LGMD2B, which is caused by dysferlin mutations. Dysferlin is critical for calcium-dependent muscle membrane repair upon mechanically- or laser-inflicted membrane damage. However, it is far from clear how dysferlin exerts its function. Therefore we analyzed the composition of dysferlin protein complexes in cultured myoblasts, myotubes and skeletal muscle tissue and identified, among others, AHNAK and calpain 3 as interaction partners. AHNAK is a giant protein with unclear function. Mutations in the protease calpain 3 cause LGMD2A. We could subsequently demonstrate that AHNAK is cleaved by calpain 3, and AHNAK fragments cleaved by calpain 3 have lost their affinity for dysferlin. In skeletal muscle of LGMD patients, AHNAK was lost in the absence of dysferlin (LGMD2B), while it accumulated when calpain 3 was defective (LGMD2A). Thus, our findings suggest that calpain 3 proteolytically regulates the dysferlin protein complex, and suggest interconnectivity between two LGMD variants. Finally we investigated the substrate spectrum of calpain 3. We found that calpain 3 mainly targets structural proteins, and is involved in local remodeling of cyto-architecture.

In summary, effective membrane maintenance requires proper coordination of two processes. First the hole needs to be patched. Second, the local cytoskeleton needs to be remodeled to allow the membrane repair vesicles to go through. Dysferlin may well coordinate these two processes.

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