1. Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency.
- Author
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Tuijnenburg P, Lango Allen H, de Bree GJ, Savic S, Jansen MH, Stockdale C, Simeoni I, Ten Berge IJM, van Leeuwen EMM, Thaventhiran JE, and Kuijpers TW
- Subjects
- Adrenal Insufficiency congenital, Ankyrin Repeat genetics, Cells, Cultured, Common Variable Immunodeficiency genetics, Ectodermal Dysplasia, Female, Humans, Immunoglobulin Class Switching genetics, Immunologic Memory, Immunophenotyping, Lymphocyte Activation, Male, Pedigree, Receptors, CXCR5 metabolism, B-Lymphocytes immunology, Common Variable Immunodeficiency immunology, Mutation genetics, NF-kappa B p52 Subunit genetics, T-Lymphocytes immunology
- Abstract
Genetic studies are identifying an increasing number of monogenic causes of Common Variable Immunodeficiency (CVID). Pathogenic variants in the C-terminus of NFKB2 have been identified in the subset of CVID patients whose immunodeficiency is associated with ectodermal dysplasia and central adrenal insufficiency. We describe 2 unrelated CVID pedigrees with 4 cases of pathogenic stop gain variants (c.1903C > T) in the ankyrin repeat domain (ARD) of NF-κB2, leading to a premature truncation of the protein at p.Arg635Term (R635X). By immunophenotyping and functional ex vivo B- and T-cell experiments we characterized the variant by reduced class-switched memory B-cell counts and immature plasmablasts, unable to produce IgG and IgA. Features of a poor proliferative T-cell response and reduced expansion of CD4
+ CXCR5+ T cells was only observed in the two clinically affected index cases without any clear clinical correlate. In conclusion, pathogenic stop variants in the ARD of NFKB2 can cause 'infection-only' CVID with an abnormal B-cell phenotype and a variable clinical penetrance., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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