Abstract
Limb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in the dysferlin gene ( DYSF ). This disease has two known pathogenic missense mutations that occur within dysferlin's C2A domain, namely C2A (W52R) and C2A (V67D) . Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlin's ability to repair cells. The failure of C2A (W52R) and C2A (V67D) to initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes β-strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1β. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving C2A (W52R) and C2A (V67D) , as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.