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 inflammasome-activating NLR receptors may contribute to MS risk.

炎性小体的遗传和功能分析表明，这种多蛋白复合物在导致多发性硬化症（MS）发作和发展的生物学机制中具有重要作用。核苷酸结合，富含亮氨酸的重复（NLR）受体响应危险信号触发特定炎症小体的激活和组装。来自326名MS患者的外显子体测序数据的鉴定在NLR家族的含1（NLRP1），NLRP3，NLRP6，NLRP7的缺失域和含4（NLRC4的NLR家族的CARD域中鉴定了17种罕见的义或无义变异。）。在2503名MS病例和1076名健康对照中对这些变异进行基因分型并没有导致各组之间的统计学差异，并且MS族内的隔离分析在很大程度上不支持这些变异与疾病的共同隔离。然而，MS患者的窝藏罕见纯合子的识别在变体NLRP1（p.Ile601Phe和p.Ser1387Ile），在一个变型NLRP3（p.Leu832Ile）导致关键氨基酸的取代为它的富含亮氨酸重复的形成域，以及几名患有NLRC4变异体（p.Arg310Ter和p.Glu600Ter）的MS患者引起蛋白质截断，提示在炎性体激活的NLR受体中罕见的改变蛋白质的变异体可能会增加MS的风险。