Novel gain-of-function mutation in dysferlin causes vesicle trafficking defect and IL-1 mediated autoinflammation

The study, posted on medRxiv, describes two infants with the same de novo DYSF mutation (p.P1449L) presenting with early-onset systemic autoinflammation and sterile lung abscesses. Mechanistically, myeloid expression of DYSF P1449L enhances COP-I binding, causing dysferlin retention in the ER-Golgi and disrupting vesicle trafficking. This leads to IL-1-mediated inflammation, expanding the known roles of dysferlin beyond muscular dystrophy into innate immune regulation. The findings suggest that DYSF mutations should be considered in undiagnosed autoinflammatory syndromes and may point to new therapeutic targets in the IL-1 pathway.