A novel CARD11 germline mutation in a Chinese patient of B cell expansion with NF-κB and T cell anergy (BENTA) and literature review

Abstract

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.

A New Missense Mutation in DPM2 Gene is Associated with a Milder Form of DPM2-CDG in Two Chinese Siblings

“…2B and 2C, G66E variant dramatically increased the expressions of DPM2 gene and protein, respectively, whereas Y23C had no signi cantly change on gene or protein. As reported previously, the patients with Y23C had severe clinical symptoms and expired before 3 years old (12), suggesting that Y23C has devastating effects. Thus, we postulate the protein level is not a critical factor for DPM2 proper function.…”

“…A protein sequence conservative analysis of mutation sites was conducted using MEGA software. The protocol used for WES was the same as described previously (12). DPM2 plasmids construction and cell transfection HCT116 cells were grown in DMEM supplemented with 10% fetal bovine serum (Gibco).…”

“…Literature review of DPM2-CDG was conducted by searching for all cases reported from 2012, the year the DPM2-CDG was rst reported (12), to 2021 with the keywords "DPM2 gene" and "congenital disorders of glycosylation".…”