Type-Specific Impacts of Protein Defects in Pathogenic NFKB2 Variants: Novel Clinical Findings From 138 Patients

The noncanonical NF-κB2 (nuclear factor kappa B subunit 2) pathway is integral in regulating immunologic responses, supervising immune function, development, and homeostasis. NFKB2 encodes the cytoplasmic precursor p100, which undergoes processing of its inhibitory C-terminal half to generate p52. Impeding C-terminal defects are well established to cause primary immunodeficiency disorder. In contrast, the mechanism of truncating N-terminal defects remains obscure.

We characterized clinical phenotypes associated with 3 distinct protein-defect types: (1) early truncations: typically occurring N-terminal relative to the nuclear localization sequence and affecting the Rel homology domain, predicting p100 expression to be halved and subsequent p52 generation by processing to be diminished; (2) central truncations: mainly affecting the ARD and predicting immediate expression of p52-like proteins and a 50% reduction of p100; and (3) C-terminal phosphorylation-/ubiquitination domain defects: causing expression of nonprocessable p100 with retained IκB-like activity and subsequently reducing generation of p52.

We performed literature research on PubMed, Clinvar, and Human Gene Mutation Database collecting clinical and immunologic data on NFKB2 patients, focusing on comparing protein-defect-specific impacts.

The highest prevalence of early-onset primary immunodeficiency disorder and antibody deficiency occurred in the CTD-defect group. In addition, endocrinological abnormalities and T-cell-mediated autoimmunity were common and frequently required immunosuppression. An extensive immunologic workup revealed patients with C-terminal defects to have pan-hypogammaglobulinemia and reduced specific antibody responses and markedly impaired B-cell differentiation, but normal to elevated T-cell counts. In contrast, pathogenic NFKB2 variants causing central or early-truncating protein defects were only partially penetrant, with ameliorated symptoms and diminished T-cell-mediated autoimmunity.

Our work defines a clear genotype-phenotype correlation for NFKB2 mutations.