Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype

Hye Sun Kuehn, Julie E. Niemela, Karthik Sreedhara, Jennifer L. Stoddard, Jennifer Grossman, Christian A. Wysocki, M. Teresa De La Morena, Mary Garofalo, Jingga Inlora, Michael P. Snyder, David B. Lewis, Constantine A. Stratakis, Thomas A. Fleisher, Sergio D. Rosenzweig

Research output: Contribution to journalArticle

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Abstract

NF-κB signaling through its NFKB1-dependent canonical and NFKB2-dependent noncanonical pathways plays distinctive roles in a diverse range of immune processes. Recently, mutations in these 2 genes have been associated with common variable immunodeficiency (CVID). While studying patients with genetically uncharacterized primary immunodeficiencies, we detected 2 novel nonsense gain-of-function (GOF) NFKB2 mutations (E418X and R635X) in 3 patients from 2 families, and a novel missense change (S866R) in another patient. Their immunophenotype was assessed by flow cytometry and protein expression; activation of canonical and noncanonical pathways was examined in peripheral blood mononuclear cells and transfected HEK293T cells through immunoblotting, immunohistochemistry, luciferase activity, real-time polymerase chain reaction, and multiplex assays. The S866R change disrupted a C-terminal NF-kΒ2 critical site affecting protein phosphorylation and nuclear translocation, resulting in CVID with adrenocorticotropic hormone deficiency, growth hormone deficiency, and mild ectodermal dysplasia as previously described. In contrast, the nonsense mutations E418X and R635X observed in 3 patients led to constitutive nuclear localization and activation of both canonical and noncanonical NF-kΒ pathways, resulting in a combined immunodeficiency (CID) without endocrine or ectodermal manifestations. These changes were also found in 2 asymptomatic relatives. Thus, these novel NFKB2 GOF mutations produce a nonfully penetrant CID phenotype through a different pathophysiologic mechanism than previously described for mutations in NFKB2.

Original languageEnglish (US)
Pages (from-to)1553-1564
Number of pages12
JournalBlood
Volume130
Issue number13
DOIs
StatePublished - Sep 28 2017

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Chemical activation
Common Variable Immunodeficiency
Phenotype
Mutation
Phosphorylation
Flow cytometry
Polymerase chain reaction
Luciferases
Adrenocorticotropic Hormone
Growth Hormone
Assays
Proteins
Blood
Genes
Wiskott-Aldrich Syndrome
Ectodermal Dysplasia
Nonsense Codon
Nuclear Proteins
Immunoblotting
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Kuehn, H. S., Niemela, J. E., Sreedhara, K., Stoddard, J. L., Grossman, J., Wysocki, C. A., ... Rosenzweig, S. D. (2017). Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood, 130(13), 1553-1564. https://doi.org/10.1182/blood-2017-05-782177

Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. / Kuehn, Hye Sun; Niemela, Julie E.; Sreedhara, Karthik; Stoddard, Jennifer L.; Grossman, Jennifer; Wysocki, Christian A.; De La Morena, M. Teresa; Garofalo, Mary; Inlora, Jingga; Snyder, Michael P.; Lewis, David B.; Stratakis, Constantine A.; Fleisher, Thomas A.; Rosenzweig, Sergio D.

In: Blood, Vol. 130, No. 13, 28.09.2017, p. 1553-1564.

Research output: Contribution to journalArticle

Kuehn, HS, Niemela, JE, Sreedhara, K, Stoddard, JL, Grossman, J, Wysocki, CA, De La Morena, MT, Garofalo, M, Inlora, J, Snyder, MP, Lewis, DB, Stratakis, CA, Fleisher, TA & Rosenzweig, SD 2017, 'Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype', Blood, vol. 130, no. 13, pp. 1553-1564. https://doi.org/10.1182/blood-2017-05-782177
Kuehn, Hye Sun ; Niemela, Julie E. ; Sreedhara, Karthik ; Stoddard, Jennifer L. ; Grossman, Jennifer ; Wysocki, Christian A. ; De La Morena, M. Teresa ; Garofalo, Mary ; Inlora, Jingga ; Snyder, Michael P. ; Lewis, David B. ; Stratakis, Constantine A. ; Fleisher, Thomas A. ; Rosenzweig, Sergio D. / Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. In: Blood. 2017 ; Vol. 130, No. 13. pp. 1553-1564.
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AU - Grossman, Jennifer

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