Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs(∗)7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853(∗)), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-κB2 is the principal protein involved in the noncanonical NF-κB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome.

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

“…43 Finally, truncation mutations of NFKB2 have been reported to cause antibody deficiency but normal levels of circulating B cells. 20 The phenotype of NFKB2 D865G/1 is significantly different from that described for human mutations in CD40, CD40LG, and TNFRSF13C (BAFFR), and indeed for truncation mutations of …”

“…Furthermore, during the course of the project, 2 other kindreds with dominant NFKB2 mutations that resulted in C-terminal truncation and antibody deficiency were described. 20 Members of the kindred described here have a heterozygous missense mutation encoding an amino acid substitution of aspartate to glycine at position 865 (NFKB2 D865G) ( Figure 4B, Table 2). Based on interrogation of dbSNP, 1000 Genomes Project, Human Genome Mutation Database, and ClinVar databases as well as other CVID kindreds within our cohort, this appears to be a novel mutation.…”

“…44,47 Defects in B-cell survival and differentiation have been reported in patients with mutations affecting BAFFR, NEMO, CD40, and CD40L as well as truncation mutations of NFKB2, but none of these cause B-cell deficiency as severe as we report here. 17,20,40,41,48 This is likely because NFKB2 D865G disrupts noncanonical signaling normally activated by several ligands, and because the mutation results in impaired canonical NF-kB signaling as well. The noncanonical defect in p52 production is a defect in response to the combined actions of CD40L, CD27, and BAFF-all ligands that normally signal via the noncanonical pathway to maintain B-cell homeostasis.…”

“…18,19 Recently, 4 individuals were described with loss-of-function mutations (C-terminal truncation of NF-kB), which resulted in antibody deficiency, normal or slight reduction of circulating B cells, and alopecia areata. 20 Here, we report an autosomal-dominant missense mutation of NFKB2. This mutation interferes with processing of p100 to p52.…”

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

“…Several candidate genes had been screened (LIF, Ikaros and Eos) but no evident aetiology could be identified. By doing whole exome sequencing, Chen et al, and then our team, managed to identify NFKB2 mutations as the plausible cause of DAVID syndrome (8,9). Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) is a pleiotropic transcription factor present in almost all cell types but its precise roles remain incompletely understood.…”