{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T07:47:36Z","timestamp":1791100056153,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2010,1,21]],"date-time":"2010-01-21T00:00:00Z","timestamp":1264032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2010,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To gain insight into the pathophysiology of an atypical familial form of an autoinflammatory disorder, characterized by autosomal\u2010dominant sensorineural hearing loss, systemic inflammation, increased secretion of interleukin\u20101\u03b2 (IL\u20101\u03b2), and the absence of any cutaneous manifestations, and to assess the functional consequences of a missense mutation identified in the leucine\u2010rich repeat (LRR) domain of NLRP3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Microsatellite markers were used to test the familial segregation of the <jats:italic>NLRP3<\/jats:italic> locus with the disease phenotype. All <jats:italic>NLRP3<\/jats:italic> exons were screened for mutations by sequencing. Functional assays were performed in HEK 293T cells to determine the effects of mutated (versus normal) NLRP3 proteins on NF\u2010\u03baB activation, caspase 1 signaling, and speck formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A heterozygous <jats:italic>NLRP3<\/jats:italic> missense mutation (p.Tyr859Cys) was identified in exon 6, which encodes the LRR domain of the protein. This mutation was found to segregate with the disease phenotype within the family, and had a moderate activating effect on speck formation and procaspase 1 processing and did not alter the inhibitory properties of NLRP3 on NF\u2010\u03baB signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This report is the first to describe a familial form of a cryopyrinopathy associated with a mutation outside of exon 3 of <jats:italic>NLRP3<\/jats:italic>. This finding, together with the known efficacy of anti\u2013IL\u20101 treatments in these disorders, underlines the importance of screening all exons of <jats:italic>NLRP3<\/jats:italic> in patients who present with atypical manifestations. In addition, the gain of function associated with this mutation in terms of activation of caspase 1 signaling was consistent with the observed inflammatory phenotype. Therefore, this study of the functional consequences of an LRR mutation sheds new light on the clinical relevance of in vitro assays.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.27326","type":"journal-article","created":{"date-parts":[[2010,1,21]],"date-time":"2010-01-21T17:18:22Z","timestamp":1264094302000},"page":"1176-1185","source":"Crossref","is-referenced-by-count":32,"title":["Functional consequences of a germline mutation in the leucine\u2010rich repeat domain of NLRP3 identified in an atypical autoinflammatory disorder"],"prefix":"10.1002","volume":"62","author":[{"given":"Isabelle","family":"J\u00e9ru","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Marlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Le 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