Journal article
A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency
Journal of clinical immunology, Vol.40(8), pp.1093-1101
11/01/2020
DOI: 10.1007/s10875-020-00842-2
PMCID: PMC7567683
PMID: 32813180
Abstract
The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of
NFKB2
have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in
NFKB2
(c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.
Details
- Title: Subtitle
- A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency
- Creators
- Hye Sun Kuehn - Building 10, Room 2C306, 10 Center Drive, MSC1508, Bethesda, MD USAAndrea Bernasconi - Garrahan HospitalJulie E. Niemela - Building 10, Room 2C306, 10 Center Drive, MSC1508, Bethesda, MD USAMaria Belen Almejun - Garrahan HospitalWilliam Alexander Franco Gallego - Universidad de AntioquiaShubham Goel - Building 10, Room 2C306, 10 Center Drive, MSC1508, Bethesda, MD USAJennifer L. Stoddard - Building 10, Room 2C306, 10 Center Drive, MSC1508, Bethesda, MD USARonald Guillermo Peláez Sánchez - Universidad de AntioquiaCarlos Andrés Arango Franco - Universidad de AntioquiaMatías Oleastro - Garrahan HospitalEyal Grunebaum - Hospital for Sick ChildrenZuhair Ballas - University of Iowa, ImmunologyCharlotte Cunningham-Rundles - Icahn School of Medicine at Mount SinaiThomas A. Fleisher - National Institutes of Health Clinical CenterJosé Luis Franco - Universidad de AntioquiaSilvia Danielian - Garrahan HospitalSergio D. Rosenzweig - National Institutes of Health Clinical Center
- Resource Type
- Journal article
- Publication Details
- Journal of clinical immunology, Vol.40(8), pp.1093-1101
- DOI
- 10.1007/s10875-020-00842-2
- PMID
- 32813180
- PMCID
- PMC7567683
- NLM abbreviation
- J Clin Immunol
- ISSN
- 0271-9142
- eISSN
- 1573-2592
- Publisher
- Springer US
- Grant note
- ; 111556934592 / ;
- Language
- English
- Date published
- 11/01/2020
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984359893902771
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