{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:33:15Z","timestamp":1786361595795,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Rheumatology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  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 (\n                  <jats:italic>DYSF<\/jats:italic>\n                  ; p.P1449L) Myeloid expression of\n                  <jats:italic>DYSF<\/jats:italic>\n                  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\u03b2 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\n                  <jats:italic>DYSF<\/jats:italic>\n                  mutations.\n                <\/jats:p>","DOI":"10.64898\/2026.08.04.26358821","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:30:21Z","timestamp":1786123821000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel gain-of-function mutation in dysferlin causes vesicle trafficking defect and IL-1 mediated autoinflammation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2316-1221","authenticated-orcid":false,"given":"Farzana","family":"Bhuyan","sequence":"first","affiliation":[{"name":"Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and 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