The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

非经典 NF-κB 通路涉及多种生物学和免疫学过程。单等位基因C末端失功能和增益的功能的突变NFKB2最近已鉴定为免疫缺陷的与普通易变免疫缺陷病（CVID）或联合免疫缺陷（CID）的表型表现的原因。在此我们报告了一个携带NFKB2杂合无义突变的家族（c.809G > A，p.W270*）。该变体与 mRNA 衰减增加和无突变 NFKB2 蛋白表达相关，导致 NFKB2 单倍体不足。我们的研究结果表明，真正的 NFKB2 单倍体不足（可能由突变 mRNA 衰减和蛋白质不稳定性导致仅野生型等位基因的转录和表达）与临床免疫缺陷有关，尽管临床外显率不完全。B 细胞发育异常、低丙种球蛋白血症、抗体反应差和非经典（但正常经典）NF-κB 通路信号异常是这种疾病的免疫学标志。这为 NFKB2 介导的免疫缺陷疾病的病理生理学增加了第三个等位基因变体。