title: 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.
authors.affiliation: King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, Denmark Hill, London, SE5 9RS, UK.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Hanson
authors.forename: Padmalal
authors.initials: P
authors.lastname: Gurugama
authors.forename: Alison
authors.initials: A
authors.lastname: Jones
authors.forename: Barnaby
authors.initials: B
authors.lastname: Clark
authors.forename: Mohammad A A
authors.initials: MA
authors.lastname: Ibrahim
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D006115:Greece; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016328:NF-kappa B