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Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations
NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a ra...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530060/ https://www.ncbi.nlm.nih.gov/pubmed/36203612 http://dx.doi.org/10.3389/fimmu.2022.973543 |
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author | Staels, Frederik De Keukeleere, Kerstin Kinnunen, Matias Keskitalo, Salla Lorenzetti, Flaminia Vanmeert, Michiel Prezzemolo, Teresa Pasciuto, Emanuela Lescrinier, Eveline Bossuyt, Xavier Gerbaux, Margaux Willemsen, Mathijs Neumann, Julika Van Loo, Sien Corveleyn, Anniek Willekens, Karen Stalmans, Ingeborg Meyts, Isabelle Liston, Adrian Humblet-Baron, Stephanie Seppänen, Mikko Varjosalo, Markku Schrijvers, Rik |
author_facet | Staels, Frederik De Keukeleere, Kerstin Kinnunen, Matias Keskitalo, Salla Lorenzetti, Flaminia Vanmeert, Michiel Prezzemolo, Teresa Pasciuto, Emanuela Lescrinier, Eveline Bossuyt, Xavier Gerbaux, Margaux Willemsen, Mathijs Neumann, Julika Van Loo, Sien Corveleyn, Anniek Willekens, Karen Stalmans, Ingeborg Meyts, Isabelle Liston, Adrian Humblet-Baron, Stephanie Seppänen, Mikko Varjosalo, Markku Schrijvers, Rik |
author_sort | Staels, Frederik |
collection | PubMed |
description | NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD). The clinical spectrum has also expanded with possible disease manifestations in almost any organ system. In silico prediction tools are often used to estimate the pathogenicity of NFKB1 variants but to prove causality between disease and genetic findings, further downstream functional validation is required. In this report, we studied 2 families with CVID and two novel variants in NFKB1 (c.1638-2A>G and c.787G>C). Both mutations affected mRNA and/or protein expression of NFKB1 and resulted in excessive NLRP3 inflammasome activation in patient macrophages and upregulated interferon stimulated gene expression. Protein-protein interaction analysis demonstrated a loss of interaction with NFKB1 interaction partners for the p.V263L mutation. In conclusion, we proved pathogenicity of two novel variants in NFKB1 in two families with CVID characterized by variable and incomplete penetrance. |
format | Online Article Text |
id | pubmed-9530060 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95300602022-10-05 Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations Staels, Frederik De Keukeleere, Kerstin Kinnunen, Matias Keskitalo, Salla Lorenzetti, Flaminia Vanmeert, Michiel Prezzemolo, Teresa Pasciuto, Emanuela Lescrinier, Eveline Bossuyt, Xavier Gerbaux, Margaux Willemsen, Mathijs Neumann, Julika Van Loo, Sien Corveleyn, Anniek Willekens, Karen Stalmans, Ingeborg Meyts, Isabelle Liston, Adrian Humblet-Baron, Stephanie Seppänen, Mikko Varjosalo, Markku Schrijvers, Rik Front Immunol Immunology NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD). The clinical spectrum has also expanded with possible disease manifestations in almost any organ system. In silico prediction tools are often used to estimate the pathogenicity of NFKB1 variants but to prove causality between disease and genetic findings, further downstream functional validation is required. In this report, we studied 2 families with CVID and two novel variants in NFKB1 (c.1638-2A>G and c.787G>C). Both mutations affected mRNA and/or protein expression of NFKB1 and resulted in excessive NLRP3 inflammasome activation in patient macrophages and upregulated interferon stimulated gene expression. Protein-protein interaction analysis demonstrated a loss of interaction with NFKB1 interaction partners for the p.V263L mutation. In conclusion, we proved pathogenicity of two novel variants in NFKB1 in two families with CVID characterized by variable and incomplete penetrance. Frontiers Media S.A. 2022-09-20 /pmc/articles/PMC9530060/ /pubmed/36203612 http://dx.doi.org/10.3389/fimmu.2022.973543 Text en Copyright © 2022 Staels, De Keukeleere, Kinnunen, Keskitalo, Lorenzetti, Vanmeert, Prezzemolo, Pasciuto, Lescrinier, Bossuyt, Gerbaux, Willemsen, Neumann, Van Loo, Corveleyn, Willekens, Stalmans, Meyts, Liston, Humblet-Baron, Seppänen, Varjosalo and Schrijvers https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Staels, Frederik De Keukeleere, Kerstin Kinnunen, Matias Keskitalo, Salla Lorenzetti, Flaminia Vanmeert, Michiel Prezzemolo, Teresa Pasciuto, Emanuela Lescrinier, Eveline Bossuyt, Xavier Gerbaux, Margaux Willemsen, Mathijs Neumann, Julika Van Loo, Sien Corveleyn, Anniek Willekens, Karen Stalmans, Ingeborg Meyts, Isabelle Liston, Adrian Humblet-Baron, Stephanie Seppänen, Mikko Varjosalo, Markku Schrijvers, Rik Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title | Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title_full | Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title_fullStr | Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title_full_unstemmed | Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title_short | Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations |
title_sort | common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous nfkb1 mutations |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530060/ https://www.ncbi.nlm.nih.gov/pubmed/36203612 http://dx.doi.org/10.3389/fimmu.2022.973543 |
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