Novel gain-of-function mutation in dysferlin causes vesicle trafficking defect and IL-1 mediated autoinflammation
Bhuyan, F.; Bradfield, C.; Roy, A.; de Jesus, A. A.; Rahman, M. A.; Schwarz, B.; Gasilina, A.; Rastegar, A.; Gaurav, S.; Friend, C. L.; Chopra, K.; Uss, K.; Kissinger, R.; Alehashemi, S.; Ganesan, S.; Brandes, N. T.; Lacroix, I. S.; Nair, V.; Leung, J. M.; Winkler, C.; Kabat, J.; Holland, S. M.; Kahn, P. J.; Kuhns, D.; Hammer, J.; Herzog, R.; Consolini, D.; Fraser, I.; Goldbach-Mansky, R.
Show abstract
De novo mutations underlying early-onset systemic autoinflammatory diseases have identified key regulators of innate immunity, including pathways that drive IL-1-mmediated inflammation. Here we describe two unrelated girls presenting in infancy with systemic inflammation and sterile lung abscesses, who harbor the same de novo gain-of-function mutation in dysferlin (DYSF; p.P1449L) Myeloid expression of DYSF P1449L enhances COP-I binding, promotes dysferlin retention in the ER-Golgi, and disrupts vesicle trafficking and membrane homeostasis. Dysferlin-mutant monocytes and M2-like macrophages exhibit ectopic perinuclear NLRP3 inflammasome activation, increased IL-1{beta} production, and inflammatory cell death. Mutant M2-like macrophages further display defects in membrane expansion, exocytosis, efferocytosis, and debris clearance, promoting neutrophil recruitment and DAMP-signal amplification that culminate in sterile abscess formation. These findings identify dysferlin as a regulator of membrane homeostasis in myeloid cells, establish defective membrane-stress adaptation as trigger of NLRP3 inflammasome activation, and define a novel IL-1 mediated autoinflammatory disease caused by gain-of-function DYSF mutations.
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