Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome

Abstract

AbstractLimb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in thedysferlingene (DYSF). This disease has two known pathogenic missense mutations that occur within dysferlin’s C2A domain, namely C2AW52Rand C2AV67D. 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 C2AW52Rand C2AV67Dto 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 C2AW52Rand C2AV67D, as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.