Format

Send to

Choose Destination
J Allergy Clin Immunol. 2017 Sep;140(3):782-796. doi: 10.1016/j.jaci.2016.10.054. Epub 2017 Jan 21.

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

Author information

1
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
2
Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
3
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
4
Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
5
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
6
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
7
Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
8
Research Programs Unit, Genome-scale Biology Program, University of Helsinki, Helsinki, Finland.
9
Department of Internal Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland.
10
Fimlab Laboratories, Tampere University Hospital, Tampere, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
11
Folkhälsan Institute of Genetics, Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
12
Research Unit of Biomedicine, University of Oulu, Oulu, Finland.
13
Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO) and MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
14
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
15
Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Competence Centre on Health Technologies, Tartu, Estonia.
16
Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
17
Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
18
Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
19
Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
20
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
21
Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. Electronic address: juha.kere@ki.se.
22
Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Abstract

BACKGROUND:

The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.

OBJECTIVE:

We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.

METHODS:

We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles.

RESULTS:

In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions.

CONCLUSION:

Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.

KEYWORDS:

B cell; Behçet disease; NFKB1; Nuclear factor κ light-chain enhancer of activated B cells; autoinflammation; hypogammaglobulinemia; p105; p50

PMID:
28115215
DOI:
10.1016/j.jaci.2016.10.054
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center