Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis
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Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis Lisa F. Popplewell 1 & Mary Encarnacion 1 & Cecily Q. Bernales 1 & A Dessa Sadovnick 1,2 & Anthony L. Traboulsee 2 & Jacqueline A. Quandt 3 & Carles Vilariño-Güell 1 Received: 29 April 2020 / Accepted: 4 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Genetic and functional analyses of the inflammasome suggest a role for this multiprotein complex in the biological mechanisms leading to the onset and progression of multiple sclerosis (MS). Nucleotide-binding, leucine-rich repeat (NLR) receptors trigger the activation and assembly of specific inflammasomes in response to danger signals. Mining exome sequencing data from 326 MS patients identified 17 rare missense or nonsense variants in NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLRP7 and NLR family CARD domain containing 4 (NLRC4). Genotyping these variants in 2503 MS cases and 1076 healthy controls did not result in statistically significant differences between groups, and segregation analysis within MS families was largely unsupportive of co-segregation of these variants with disease. However, the identification of MS patients harboring rare homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile), a variant in NLRP3 (p.Leu832Ile) resulting in the substitution of a critical amino acid for the formation of its leucine-rich repeat domain, and several MS patients with NLRC4 variants (p.Arg310Ter and p.Glu600Ter) causing protein truncations suggest that rare protein-altering variants in inflammasomeactivating NLR receptors may contribute to MS risk. Keywords Multiple sclerosis . NOD-like receptors . NLR . Inflammasome . Genetic . Variant . Mutation
Inflammasomes are intracellular multiprotein complexes that mediate innate immunity in response to pathogen or dangerassociated molecular patterns. The formation and activation of the inflammasome is triggered by nucleotide-binding, leucinerich repeat (NLR)-containing protein sensors which recognize diverse molecular patterns. Activation of the inflammasome leads to a proteolytic cascade resulting in the activation and secretion of interleukin (IL)-1B and IL-18, initiating a proinflammatory response and inducing pyroptosis (Olcum Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00251-020-01170-w) contains supplementary material, which is available to authorized users. * Carles Vilariño-Güell [email protected] 1
Department of Medical Genetics, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
2
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
3
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada
et al. 2020). Mutations in inflammasome components can cause pathogenic inflammatory syndromes, including multiple sclerosis (MS). Homozygote NLR family pyrin domain cont
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