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

作者全名："Wang, Li; Wen, Wen; Deng, Mengyue; Li, Yue; Sun, Gan; Zhao, Xiaodong; Tang, Xuemei; Mao, Huawei"

作者地址："[Wang, Li; Wen, Wen; Deng, Mengyue; Li, Yue; Sun, Gan; Zhao, Xiaodong; Tang, Xuemei] Chongqing Med Univ, Dept Pediat Res Inst,Natl Clin Res Ctr Child Hlth, Chongqing Key Lab Child Infect & Immun,China Int, Minist Educ,Key Lab Child Dev & Disorders,Childre, Chongqing, Peoples R China; [Wang, Li; Zhao, Xiaodong; Tang, Xuemei] Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China; [Mao, Huawei] Capital Med Univ, Dept Immunol, Minist Educ,Natl Ctr Childrens Hlth, Key Lab Major Dis Children,Beijing Childrens Hosp, Beijing, Peoples R China"

通信作者："Tang, XM (corresponding author), Chongqing Med Univ, Dept Pediat Res Inst,Natl Clin Res Ctr Child Hlth, Chongqing Key Lab Child Infect & Immun,China Int, Minist Educ,Key Lab Child Dev & Disorders,Childre, Chongqing, Peoples R China.; Tang, XM (corresponding author), Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China.; Mao, HW (corresponding author), Capital Med Univ, Dept Immunol, Minist Educ,Natl Ctr Childrens Hlth, Key Lab Major Dis Children,Beijing Childrens Hosp, Beijing, Peoples R China."

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000670250500001

JCR分区：Q1

影响因子：7.3

年份：2021

卷号：12

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：NLRC4; novel mutation; autoinflammatory disease; mild phenotype; urticaria

摘要："Background NOD-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. Methods We 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. Results We 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-1 beta 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. Conclusion We 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."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81971547]; Research Fund for Outstanding Youth Scholar of Chongqing Talents [CQYC201905003]; High-level Medical Reserved Personnel Training Project of Chongqing [2019181]

基金资助正文："This work was supported partly by the National Natural Science Foundation of China (Grant number 81971547), the Research Fund for Outstanding Youth Scholar of Chongqing Talents (Grant number CQYC201905003), and the High-level Medical Reserved Personnel Training Project of Chongqing (Grant number 2019181)."