A Novel Mutation in the NBD Domain of NLRC4 Causes Mild Autoinflammation With Recurrent Urticaria

Abstract

BackgroundNOD-like receptor family CARD-containing 4 protein (NLRC4) is a cytosolic protein that forms an inflammasome in response to flagellin and type 3 secretion system (T3SS) proteins from invading Gram-negative bacteria. NLRC4 mutations have been recently identified in early-onset severe autoinflammatory disorders. In this study, we reported a novel mutation in NLRC4 in two Chinese patients, who manifested with recurrent urticaria and arthralgia.MethodsWe summarized the clinical data of the two patients. Gene mutations were identified by whole-exome sequencing (WES). Swiss-PdbViewer was used to predict the pathogenicity of the identified mutations. Cytokine levels and caspase-1 activation were detected in the patient PBMCs with lipopolysaccharide (LPS) stimulation. All previously published cases with NLRC4 mutations were reviewed.ResultsWe identified a missense heterozygous mutation (c.514G>A, p.Gly172Ser), which was located in the highly conserved residue of nucleotide-binding domain (NBD) of NLRC4. The mutation did not alter the expression of NLRC4 protein, but induced considerably much higher production of IL-1β and IL-6 in patient PBMCs than in healthy controls after LPS stimulation. Four NLRC4 inflammasomopathy phenotypes have been described, with severe inflammatory diseases including macrophage activation syndrome, enterocolitis and NOMID in patients with mutations in the NBD and HD1 domains, whereas a mild clinical phenotype was associated with two mutations in the WHD domain of NLRC4.ConclusionWe identified a novel mutation in the NBD domain, and the patients just presented with a mild inflammatory phenotype. Thus, our findings reinforce the diversity of NLRC4 mutations and expand the clinical spectrum of associated diseases.

Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18

“…However, NLRC4-MAS/AIFEC exhibits more elevated serum IL-18 than does FCAS4 or NOMID (10 3 –10 5 vs . 10 3 pg/mL), thereby demonstrating that the levels of serum IL-18 are likely correlated with disease severity ( 45 – 52 , 75 , 76 , 80 ) ( Table 1 ).…”

“…An NLRC4 gain-of-function mutation leads to the spontaneous activation of NLRC4 inflammasome and causes autoinflammation. To date, 13 pathogenic variants have been reported (45-52, [73][74][75][76][77][78][79][80]. Most of them are located around the ADP-binding site, which abrogates nucleotide-binding autoinhibitory conformation.…”

“…An argument initially was whether NBD and HD1 mutations were likely associated with NLRC4-MAS/AIFEC and the NOMID-phenotype, and whether WHD mutations were associated with the FCAS phenotype (72). However, in recent familial cases of the FCAS phenotype, patients harbored the novel pathogenic variant in the NBD domain (80), which indicated that a genotype-phenotype correlation is not as clear as might have been expected. Serum IL-18 is markedly and chronically elevated in NLRC4-AID.…”

Inflammasome activation: from molecular mechanisms to autoinflammation

“…The severity of symptoms range from AIFEC and NLRC4‐MAS, which require frequent hospitalisations for life‐threatening episodes, to FCAS4 with milder phenotypes of urticarial rash and arthritis 117,118 . However, progress in this field is slow as there are relatively few known patients with pathogenic NLRC4 mutations 119 …”

“… 117 , 118 However, progress in this field is slow as there are relatively few known patients with pathogenic NLRC4 mutations. 119 …”