Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10⁻¹⁵). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

中文翻译：

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生化有害的人类 NFKB1 变体是常见可变免疫缺陷的常染色体显性遗传形式的基础

常染色体显性遗传 (AD) NFKB1 缺乏被认为是常见可变免疫缺陷 (CVID) 最常见的遗传病因。然而， NFKB1之间的因果关系由于生化表征和富集分析不足，变异和 CVID 尚未在实验和基因上得到证实。我们表明，NFKB1 缺陷型 HEK293T 细胞（缺乏 p105 及其裂解形式 p50）与 κB 报告基因、NFKB1/p105 和同源二聚化缺陷型 RELA/p65 突变体的共转染导致 p50:p65 异二聚体依赖性和 p65： p65 同源二聚体独立的转录激活。我们发现 CVID 或相关疾病患者的 90 种变异中有 59 种是功能丧失或畸形。相比之下，普通人群或患有不相关疾病的患者中的 260 种变异中有 258 种是中性的。没有一个有害变体显示出负优势。有害NFKB1的富集CVID 患者的变异具有选择性且高度显着（P = 2.78 × 10 ^-15）。因此，破坏 NFKB1/p50 转录活性的NFKB1变体是单倍体不足导致 AD CVID 的基础，而该测定中的中性变体不应被视为因果关系。