Brief reportCombined immunodeficiency caused by a novel homozygous NFKB1 mutation
Introduction
The nuclear factor-κB (NF-κB) signaling pathway plays a major role in mediating multiple cellular events including immune and inflammatory responses, lymphocyte development, cell growth, and programmed death.1 The NF-κB system consists of 5 structurally related proteins that function in the classical or alternative NF-κB pathways and sense different receptors, but share significant cross-talking.2, 3, 4 The pathway members consist of NFKB1 (p50 and its precursor, p105), NFKB2 (p52 and its precursor, p100), transcription factor p65, REL-associated protein A ([RelA] p65), RelB, and c-Rel, all bound to each other in a dimerized form and sequestered in the cytoplasm by the inhibitor of NF-κB. On activation of the classical pathway by Toll-like receptors, B- or T-cell receptors, the inhibitor of NF-κB kinase enzyme complex is recruited, initiating phosphorylation and degradation events that ultimately lead to formation of the transcription factor NFKB1 heterodimer (p50/RelA) that can readily migrate into the nucleus.5,6 Proteolytic processing of p105 to p50 is a key step in this cascade and is regulated by the ubiquitin-proteasome system.7
A variety of immunodeficiencies have been shown to arise from mutations in the classical as well as alternative pathway components.8, 9, 10, 11, 12, 13
Recently, heterozygous mutations in NFKB1 resulting in haploinsufficiency have been identified in a relatively large proportion of patients with common variable immunodeficiency.14
We report here the first case of homozygous NFKB1 deficiency in a patient with severe life-threatening infections and combined immunodeficiency.
Section snippets
Results and discussion
NFKB1 haploinsufficiency has been implicated in the pathogenesis of common variable immunodeficiency.14, 15, 16, 17 Patients typically present during childhood, teenage years, or later, with repeated sinopulmonary infections as well as occasional autoimmune or lymphoproliferative manifestations.15,16
Unlike patients with NFKB1 haploinsufficiency, the patient described herein presented early in life with symptoms reminiscent of severe combined immunodeficiency. The patient was born at term after
References (25)
- et al.
30 years of NF-kappaB: a blossoming of relevance to human pathobiology
Cell
(2017) - et al.
NF-kappaB pathway and the Goldilocks principle: lessons from human disorders of immunity and inflammation
J Allergy Clin Immunol
(2019) - et al.
Nuclear factor-kappaB1: regulation and function
Int J Biochem Cell Biol
(2008) - et al.
The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity
Cell
(2016) - et al.
A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO)
Am J Hum Genet
(2000) - et al.
Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans
J Allergy Clin Immunol
(2018) - et al.
Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency
Am J Hum Genet
(2015) - et al.
The complete exon-intron structure of the 156-kb human gene NFKB1, which encodes the p105 and p50 proteins of transcription factors NF-kappa B and I kappa B-gamma: implications for NF-kappa B-mediated signal transduction
Genomics
(1995) - et al.
The death domain of NF-kappa B1 p105 is essential for signal-induced p105 proteolysis
J Biol Chem
(2002) - et al.
Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis
J Biol Chem
(2001)
Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses
Cell
Coordination between NF-kappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues
Blood
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This work was supported by Immunodeficiency Canada’s Distinguished Professorship in Immunology (C.M.R.), the Program for Immunogenomics and the Canadian Centre for Primary Immunodeficiency (C.M.R.), and the Jeffrey Modell Foundation and Immunodeficiency Canada (C.M.R.).
Disclosure of potential conflict of interest: D. Merico is a full-time employee of Deep Genomics and is entitled to a stock option. The rest of the authors declare that they have no relevant conflicts of interest.