Clinical heterogeneity of NLRP12-associated autoinflammatory diseases  

作　　者：Yue Li Mengyue Deng Yulu Li Xiaolan Mao Shi Yan Xuemei Tang Huawei Mao 

机构地区：[1]Department of Rheumatology and Immunology,Children's Hospital of Chongqing Medical University,National Clinical Research Center for Child Health and Disorders,Ministry of Education Key Laboratory of Child Development and Disorders,Chongqing Key Laboratory of Child Infection and Immunity,Chongqing 400014,China [2]Department of Rheumatology and Immunology,Children's Hospital of Chongqing Medical University,Chongqing 400014,China

出　　处：《Genes & Diseases》2023年第3期1090-1100,共11页基因与疾病（英文）

基　　金：supported in part by the National Key Research and Development Program of China(No.2021YFC2702005);National Natural Science Foundation of China(No.81971547);the Research Fund for Outstanding Youth Scholar of Chongqing Talents(No.CQYC201905003);the High-level Medical Reserved Personnel Training Project of Chongqing(No.2019181).

摘　　要：Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in NLRP12 cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far, very few patients with NLRP12-AID have been identified worldwide;therefore, data on the clinical phenotype and genetic profile are limited. In this study, we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of NLRP12, including 2 novel null mutations. Of the patients, some with same mutations showed different clinical features. Compared to healthy controls, the increased levels of cytokines were revealed in the patients' plasmas, as well as in the supernatants of patients’ cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression;but decreased level of NLRP12 protein was shown in the null mutations. And in vitro expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively, this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum, and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice, especially for patients presenting with periodic fever but no other genetic cause identified.

关 键 词：Autoinflammatory diseases Fanilial cold autoinflammatory syndr ome type 2(FCAS2) NLRP12-Associated autoinflammatory disease(NLRP12-AID) Nod-like receptor family pyrin domain-containing protein 12(NLRP12) Nuclear factor-Kappa B(NF-kB) 

分 类 号：R72[医药卫生—儿科]