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

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

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