CARD11基因非经典区域突变所致免疫缺陷2例的临床和免疫特征

The clinical and immune features of patients with CARD11 mutations located in atypic domain

目的报道2例CARD11基因非经典区域突变所致免疫缺陷的临床和免疫特征。方法总结2例CARD11突变患儿的临床特征;采用全外显子组测序及Sanger测序技术寻找其基因突变,采用体外实验进行致病性验证,探讨其致病机制;采用流式细胞术等技术分析其免疫特征。结果2例患儿均表现为反复呼吸道感染和过敏性疾病。例1主要表现为反复扁桃体炎、支气管炎,变应性鼻炎,发热时偶伴腹痛、关节痛;例2主要表现为反复呼吸道感染、偶发特应性皮炎及变应性结膜炎。2例均为CARD11基因杂合突变,突变位点分别为c.2542C>T(p.R848C)和c.2036A>T(p.Q679L)。c.2542C>T于2019年报道,致病机制未明;c.2036A>T既往未见报道。在293T细胞系中分别过表达携带有2种突变的CARD11蛋白,与野生型对比,2种突变蛋白对下游NF-κB通路的激活较野生型弱,提示2种突变均导致功能缺失。结论本文报告的CARD11基因突变与既往报道的经典区域突变的特征不同,丰富了CARD11基因缺陷疾病的临床和免疫特征。

Objective To report and summarize the clinical and immune features of two patients with CARD11 mutations,which are not located in CARD domain or CC domain of the gene.Methods Two atypical CARD11 mutation patients were enrolled,and their clinical and immune features were summarized.The mutations were tested by whole exon sequencing and confirmed by Sanger sequencing.Flow cytometry was used to figure out the immune phenotypes,while in vitro experiments were performed to detect the pathogenicity and pathogenic mechanism of the mutations.Results The two patients had recurrent respiratory infection and allergic diseases.Patient 1(P1)presented with recurrent tonsillitis,bronchopneumonia,allergic rhinitis and occasional abdominal pain or joint pain together with fever.Patient 2(P2)presented with recurrent upper respiratory infection,occasional atopic dermatitis and allergic conjunctivitis.Both of the two patients had heterozygous mutation in the gene of CARD11.The mutation sites were c.2542C>T(p.R848C)for P1 and c.2036A>T(p.Q679L)for P2.c.2542C>T was reported in 2019 and c.2036A>T had not been reported before.The two mutant CARD11 proteins showed less stimulation of the NF-κB signal pathway compared with WT CARD11 protein when overexpressed in 293T cells,which indicates that the mutations would lead to loss of function(LOF).Conclusion The characteristics of this novel CARD11 mutation are different from those of mutations in typical sites,which enriches the clinical and immune features of CARD11 deficiency.