Novel NFKB2 Mutation in Early-Onset CVID

Abstract

Common variable immunodeficiency (CVID) is heterogeneous, clinically, immunologically and genetically. The majority of genetic mechanisms leading to CVID remain elusive. We studied a Greek Cypriot family of non-consanguineous parents. Two children were diagnosed with CVID at an early age. Whole exome sequencing revealed 8bp deletion in the C-terminal part of NFKB2 gene associated with disease. The mutation leads to a frameshift (p.Asp865Valfs*17) altering 17 C-terminal amino acids from residue 865, and creating a premature stop-codon resulting in a truncated protein, 19 amino acids shorter than wild type (p100Δ19). We validated the results with Dye-termination sequencing and Western blot, and confirmed that the conserved residue at 866 is mutated from serine to arginine in p100Δ19, leaving the mutant protein unphosphorylated at this critical regulatory position. Consequently, NFKB2/p100 processing and nuclear translocation were abrogated. Using flow cytometry, we further demonstrated that there was a reduction in B cells (CD19+), switched memory B cells (CD27+IgD-) and T follicular helper (Tfh) cells (both CD4+CXCR5+ and CD4+CXCR5Hi) in a CVID patient with NFKB2/p100Δ19, compared to healthy controls. These data support the notion that the non-canonical NFκB pathway plays an important role in B cell differentiation and the development of Tfh cells, and may pave the way for better understanding of the pathology of CVID.

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency

“…59 In addition, NFKB2 haploinsufficiency has been acknowledged as the disease-causing mechanism of CVID-associated NFKB2 mutations. [46][47][48][49][50][51] Furthermore, several reports have supported a functional haploinsufficiency as the predominant disease mechanism associated with various primary immunodeficiencies and autoimmune phenotypes caused by mutations in TACI, 60,61 CTLA4, 15,62 NFAT5 63 (MIM: 04708), VAV1 64 (MIM: 164875), GATA2 65 (MIM: 137295), and others. Thus haploinsufficiency, frequently associated with incomplete penetrance, appears as a recurrent paradigm and emphasizes the requirement for accurate gene regulation within the immune system.…”

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

“…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. Two other groups also reported NFKB2 mutations in patients with similar phenotypes making the involvement of NFKB2 in DAVID syndrome highly likely even if the endocrine phenotype was not systematically studied (10,11). However the precise mechanisms whereby this factor may lead to endocrine deficits remain unclear.…”

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

“…The genes and the pathways identified in this study may be further pursued by studies with larger sample size and functional studies. In addition to whole genome-sequencing, recently exome-sequencing identified additional mutations that are related or causative in individual CVID patients, such as the newly identified mutations in genes NLRP12 [53], NFKB2 [54], ITPKB [55] and RAG1 [56]. A recent genetic study using whole exome-sequencing and comparative genomic hybridization array identified multiple heterozygous mutations and deletions in gene IKZF1 responsible for a form of CVID with drastically reduced number of B cells.…”