Functional consequences of a germline mutation in the leucine-rich repeat domain of NLRP3 identified in an atypical autoinflammatory disorder

Arthritis and Rheumatism
I JéruS Amselem

Abstract

To gain insight into the pathophysiology of an atypical familial form of an autoinflammatory disorder, characterized by autosomal-dominant sensorineural hearing loss, systemic inflammation, increased secretion of interleukin-1beta (IL-1beta), and the absence of any cutaneous manifestations, and to assess the functional consequences of a missense mutation identified in the leucine-rich repeat (LRR) domain of NLRP3. Microsatellite markers were used to test the familial segregation of the NLRP3 locus with the disease phenotype. All NLRP3 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-kappaB activation, caspase 1 signaling, and speck formation. A heterozygous NLRP3 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-kappaB signaling. This report is the first to describe a familial form of a cryopyrinopathy associated with a mutation out...Continue Reading

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Citations

Dec 24, 2011·Journal of Clinical Immunology·Hidenori OhnishiNaomi Kondo
Dec 20, 2015·Neurology·Christopher J SchwarzbachChristian Blahak
Aug 14, 2012·Autoimmunity Reviews·Isabelle Koné-Paut, Maryam Piram
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May 27, 2021·Nature Reviews. Rheumatology·Ivona Aksentijevich, Oskar Schnappauf

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