Rabbit Anti-DYSF monoclonal antibody, clone KG16-65

Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.

Mutations in the gene encoding dysferlin (DYSF) cause limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy (MM). We were able to examine eight patients suspected of LGMD2B clinically, histochemically. The genotype was determined in every case. We found sarcolemmal and interstitial amyloid deposits in four muscle sections. All of the mutations associated with amyloid were located in the N-terminal region of dysferlin, and dysferlin clearly proved to be a component of the amyloid deposits. Dysferlin-deficient muscular dystrophy is the first muscular dystrophy in which amyloidosis is involved. This fact must be considered in the process of developing therapeutic strategies. The influence of the amyloid deposits on the pathogenesis of the disease and the possible involvement of other organs in the progressive course are as yet unclear.