CARD11基因中的种系功能获得(GOF)突变导致一种罕见的原发性免疫缺陷疾病,称为具有NF-κB和T细胞无反应性(BENTA)的B细胞扩增。受影响的患者存在多克隆扩增的B细胞,淋巴结病,脾肿大.在这里,我们报道了一个新的种系框内三碱基对缺失(c.1030_1032del,p.K344del)在非典型BENTA患者的CARD11基因中,表现为反复发烧和B细胞淋巴细胞增多。这个突变遗传自他母亲,临床上无症状,童年时反复呼吸道感染。体外功能分析表明,该变异体降低了CARD11蛋白的表达水平,激活了NF-κB信号通路,如RNA测序分析所示,导致在用突变体CARD11(K344del-CARD11)转染的HCT116细胞中几种NF-κB靶基因转录本的更高表达。据我们所知,仅有23例BENTA患者被鉴定出在CARD11中携带7种不同的GOF突变.患者临床表现高度异质性,基因型与表型之间无显著相关性。总之,我们发现了一个新的框内3个碱基对缺失,它可能是一个中国家族非典型BENTA发病的原因.我们的研究扩展了CARD11基因的突变谱,可能有助于理解由CARD11突变引起的疾病和BENTA的临床管理。
Germline gain-of-function (GOF) mutations in the CARD11 gene lead to a rare primary immunodeficiency disease known as B cell expansion with NF-κB and T cell anergy (BENTA). Affected patients present with a polyclonal expansion of B cells, lymphadenopathy, and splenomegaly. Herein, we report a novel germline in-frame three base-pair deletion (c.1030_1032del, p.K344del) in the CARD11 gene in a patient with atypical BENTA, presenting with a recurrent fever and B cell lymphocytosis. This mutation was inherited from his mother, who is clinically asymptomatic and had a recurrent respiratory tract infection in her childhood. In vitro functional analysis demonstrated that this variant decreased the expression level of the CARD11 protein and activated the NF-κB signal pathway, leading to a higher expression of several NF-κB target gene transcripts in HCT116 cells transfected with mutant CARD11 (K344del-CARD11) as revealed by RNA sequencing analysis. To our knowledge, only 23 BENTA patients have been identified and carried seven distinct GOF mutations in CARD11. The clinical manifestations of patients are highly heterogeneous and there was no significant correlation between genotype and phenotype. In summary, we identified a novel in-frame three base-pair deletion that may be responsible for the pathogenesis of atypical BENTA in a Chinese family. Our study expands the mutational spectrum of the CARD11 gene and may be helpful in the understanding of diseases caused by CARD11 mutations and the clinical management of BENTA.