Nuclear factor κB mutations in human subjects: The devil is in the details

Fliegauf, Manfred; Grimbacher, Bodo

doi:10.1016/j.jaci.2018.06.050

Cited by 20 publications

(27 citation statements)

References 11 publications

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“…NFKB1 variants can be divided into four main groups: (1) haploinsufficiency mutations such as nonsense or frameshift mutations in the N-terminal part, typically cause severely truncated, non-functional proteins which probably undergo rapid decay; (2) “precursor skipping mutations” leading to truncation in the central part of p105 and cause expression of p50-like mutant proteins; (3) missense mutations in the N-terminal half, affecting both p105 and p50 and (4) missense variants in the C-terminal part, affecting only p105 (23).…”

Section: Introductionmentioning

confidence: 99%

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

et al. 2019

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Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in NFKB1 in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of NFKB1 mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19+CD27+). Among all tested genes, NFKB1 alterations were the most common monoallelic cause of antibody deficiency in our cohort.

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Section: Introductionmentioning

confidence: 99%

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

et al. 2019

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“…We report a novel mutation of NFKB1 in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been reported in previously described NFKB1 cases (Boztug et al 2016;Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018).…”

Section: Introductionmentioning

confidence: 73%

“…Mutations in the RHD has been reported in a number of families with variable clinical phenotype. In a Dutch-Australian family with CVID, a splice-site mutation was found to cause in-frame skipping of exon 8 which lead to degradation of the altered protein (Fliegauf and Grimbacher 2018). Similarly, 2 other families with heterozygous frameshift mutations in RHD were found to have decreased expression of p50.…”

Section: Discussionmentioning

confidence: 97%

“…Similarly, 2 other families with heterozygous frameshift mutations in RHD were found to have decreased expression of p50. Haploinsufficiency of NFKB1 in these 3 families presented with a heterogeneous spectrum of illness including hypogammaglobulinemia, recurrent sinopulmonary infections, autoimmunity, skin lesions, colitis, lymphoproliferation, and malignancy (Fliegauf and Grimbacher 2018). Interestingly, 1 of the patients in the New Zealand family with a heterozygous frameshift mutation (c.465dupA) in exon 7, presented with similar symptoms as our patient, consisting of thrombocytopenia, hemolytic anemia, and neutropenia from the young age of 2 years in the absence of other symptoms (Fliegauf and Grimbacher 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple recent studies have identified variants in NFKB1 as a monogenic cause of immunodeficiency/ immune dysregulation (Table 2) (Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018). Patients display a wide range of phenotypic heterogeneity including recurrent sinopulmonary infections, viral and fungal infections, autoimmunity, lymphoproliferation, and malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy

Duan

Feanny

2019

LymphoSign Journal

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Background: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) signaling pathway is a critical regulator of many important adaptive and innate immune responses. The NF-κB transcription factor family consists of 5 structurally related core proteins, one of which is NFKB1. Mutations in the NFKB1 gene has been reported in patients with common variable immune deficiency (CVID) as well as with a large spectrum of clinical features including recurrent viral, bacterial, and fungal infections, autoimmunity, inflammation, and malignancy. Aim: We describe the clinical characteristics of a pediatric patient with a novel mutation in NFKB1. Methods: Patient informed consent was obtained in accordance with approved protocols from the Research Ethics Board at the Hospital for Sick Children. Gene panel testing was employed to identify the immune aberration. Results: Our patient, a previously well 18-month-old boy of Philippines descent, presented with multi-lineage cytopenias (thrombocytopenia, hemolytic anemia, neutropenia), splenomegaly, and lymphadenopathy. He did not have prior history of recurrent infections. Immunological work-up showed normal numbers of T and B cells, normal quantitative immunoglobulins, and adequate vaccination titres. Gene panel testing revealed a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene. Due to persistent cytopenias unresponsive to steroids and IVIG, he was started on Sirolimus with improvement in symptoms. Conclusion: NFKB1 encodes for p105, which is processed to generate the active p50 transcription factor that can interact with different proteins to activate or inhibit downstream signaling. Our patient was found to have a missense mutation in the Rel homology domain (RHD) of p50, which has distinct functions including DNA binding, protein dimerization, and inhibitory protein binding. The clinical presentation described here broadens the scope of characteristics associated with heterozygous NFKB1 mutations. Statement of novelty: We report a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been previously reported.

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Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Schnappauf

Aksentijevich

2020

Journal of Leukocyte Biology

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NF-B is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-B mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-B is regulated through interactions with I B inhibitory proteins, which are in turn regulated by the inhibitor of B kinase (IKK) complex. Together, these 3 components form the core of the NF-B signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-B pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-B is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-B pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-B pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

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Nuclear factor κB mutations in human subjects: The devil is in the details

Cited by 20 publications

References 11 publications

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1

Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

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