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

Background: The non-canonical NF-κB2 pathway is integral in regulating immunological 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 PID. In contrast, the mechanism of truncating N-terminal defects remains obscure.

Objective: We characterized clinical phenotypes associated with three distinct protein-defect types: (I) early truncations: typically occurring N-terminal relative to the NLS and affecting the RHD, predicting p100 expression to be halved and subsequent p52 generation by processing to be diminished (II) Central truncations: mainly affecting the ARD and predicting immediate expression of p52-like proteins and a 50% reduction of p100; and (III) C-terminal phosphorylation-/ubiquitination domain defects: causing expression of non-processable p100 with retained IκB-like activity and subsequently reducing generation of p52.

Methods: We performed literature research on PubMed, Clinvar and HGMD collecting clinical and immunological data on NFKB2 patients, focusing on comparing protein-defect-specific impacts.

Results: The highest prevalence of early-onset PID and antibody deficiency occurred in the CTD-defect group. Additionally, endocrinological abnormalities and T-cell-mediated autoimmunity were common and frequently required immunosuppression. An extensive immunological 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.

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