Novel heterozygous mutation in NFKB2 in a patient with predominantly antibody deficiency
Abstract
Background: The Nuclear Factor-kappa B (NF-kB) signaling pathway plays a critical role in regulating a wide range of cellular processes such as immune function, inflammation, and tumor regulation. There are two major pathways that play a role in NF-kB activation: the canonical NF-kB1 pathway and the non-canonical NF-kB2 pathway. Abnormalities in non-canonical NF-κB2 signaling are linked with significant impairments in the immune system, mainly B cell maturation, antibody production, as well as T helper and regulatory T cell function through its effect on germinal center regulation.
Methods: Our patient’s medical record was analyzed retrospectively, including her medical history, results from immune laboratory tests, and genetic analyses.
Results: We present a 16-year-old female with a history of chronic cough complicated with episodes of hemoptysis and diagnosed with bronchiectasis secondary to common variable immunodeficiency. Whole exome sequencing analysis revealed a novel heterozygous variant in the NFKB2 gene (NM_001077494.3), c.931C>T resulting in p.Arg311Cys.
Conclusion: The presence of NFKB2 mutations can lead to the development of early-onset common variable immunodeficiency.
Statement of Novelty: We have identified a novel variant in the NFKB2 gene associated with antibody deficiency.
Get full access to this article
View all available purchase options and get full access to this article.
REFERENCES
Aird A., Lagos M., Vargas-Hernández A., Posey J.E., Coban-Akdemir Z., Jhangiani S., Mace E.M., Reyes A., King A., Cavagnaro F., Forbes L.R., Chinn I.K., Lupski J.R., Orange J.S., and Poli M.C. (2019). Novel heterozygous mutation in NFKB2 is associated with early onset CVID and a functional defect in NK cells complicated by disseminated CMV infection and severe nephrotic syndrome. Front. Pediatr. 7: 303.
Bogaert D.J.A., De Bruyne M., Debacker V., Depuydt P., De Preter K., Bonroy C., Philippé J., Bordon V., Lambrecht B.N., Kerre T., Cerutti A., Vermaelen K.Y., Haerynck F., and Dullaers M. (2017). The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives. Haematologica, 102(1): 192–202.
Bonilla F.A., Barlan I., Chapel H., Costa-Carvalho B.T., Cunningham-Rundles C., De La Morena M.T., Espinosa-Rosales F.J., Hammarström L., Nonoyama S., Quinti I., Routes J.M., Tang M.L.K., and Warnatz K. (2016). International consensus document (ICON): Common variable immunodeficiency disorders. J. Allergy Clin. Immunol. Pract. 4(1): 38–59.
Chen K., Coonrod E.M., Kumánovics A., Franks Z.F., Durtschi J.D., Margraf R.L., Wu W., Heikal N.M., Augustine N.H., Ridge P.G., Hill H.R., Jorde L.B., Weyrich A.S., Zimmerman G.A., Gundlapalli A.V., Bohnsack J.F., and Voelkerding K.V. (2013). Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am. J. Hum. Genet. 93(5): 812–824.
De Leo P., Gazzurelli L., Baronio M., Montin D., Di Cesare S., Giancotta C., Licciardi F., Cancrini C., Aiuti A., Plebani A., Cicalese M.P., Lougaris V., and Fousteri G. (2020). NFKB2 regulates human Tfh and Tfr pool formation and germinal center potential. Clin Immunol. 210: 108309.
De Valles-Ibáñez G., Esteve-Solé A., Piquer M., González-Navarro E.A., Hernandez-Rodriguez J., Laayouni H., González-Roca E., Plaza-Martin A.M., Deyà-Martínez Á., Martín-Nalda A., Martínez-Gallo M., García-Prat M., Del Pino-Molina L., Cuscó I., Codina-Solà M., Batlle-Masó L., Solís-Moruno M., Marquès-Bonet T., Bosch E., López-Granados E., Aróstegui J.I., Soler-Palacín P., Colobran R., Yagüe J., Alsina L., Juan M., Casals F., and Casals F. (2018). Evaluating the genetics of common variable immunodeficiency: Monogenetic model and beyond. Front. Immunol. 9: 636.
Gereige J.D. and Maglione P.J. (2019). Current understanding and recent developments in common variable immunodeficiency associated autoimmunity. Front. Immunol. 10: 2753.
Klemann C., Camacho-Ordonez N., Yang L., Eskandarian Z., Rojas-Restrepo J.L., Frede N., Bulashevska A., Heeg M., Al-Ddafari M.S., Premm J., Seidl M., Ammann S., Sherkat R., Radhakrishnan N., Warnatz K., Unger S., Kobbe R., Hüfner A., Leahy T.R., Ip W., Burns S.O., Fliegauf M., and Grimbacher B. (2019). Clinical and immunological phenotype of patients with primary immunodeficiency due to damaging mutations in NFKB2. Front. Immunol. 10: 297.
Kotlinowski J., Bukowska-Strakova K., Koppolu A., Kosińska J., Pydyn N., Stawinski P., Wilamowski M., Nowak W., Józkowicz A., Baran J., Płoski R., and Jura J. (2019). A novel monoallelic nonsense mutation in the NFKB2 gene does not cause a clinical manifestation. Front. Genet. 10: 140.
Kuehn H.S., Niemela J.E., Sreedhara K., Stoddard J.L., Grossman J., Wysocki C.A., De La Morena M.T., Garofalo M., Inlora J., Snyder M.P., Lewis D.B., Stratakis C.A., Fleisher T.A., and Rosenzweig S.D. (2017). Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood, 130(13): 1553–1564.
Lee C.E., Fulcher D.A., Whittle B., Chand R., Fewings N., Field M., Andrews D., Goodnow C.C., and Cook M.C. (2014). Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood, 124(19): 2964–2972.
Lindsley A.W., Qian Y., Valencia C.A., Shah K., Zhang K., and Assa’ad A. (2014). Combined immune deficiency in a patient with a novel NFKB2 mutation. J. Clin. Immunol. 34(8): 910–915.
Lorenzini, T., Fliegauf, M., Klammer, N., Frede, N., Proietti, M., Bulashevska, A., Camacho-Ordonez, N., Varjosalo, M., Kinnunen, M., de Vries, E., van der Meer, J.W.M., Ameratunga, R., Roifman, C.M., Schejter, Y.D., Kobbe, R., Hautala, T., Atschekzei, F., Schmidt, R.E., Schröder, C., Stepensky, P., Shadur, B., Pedroza, L.A., Flier, M.V.D., Martínez-Gallo, M., Gonzalez-Granado, L.I., Allende, L.M., Shcherbina, A., Kuzmenko, N., Zakharova, V., Neves, J.F., Svec, P., Fischer, U., Ip, W., Bartsch, O., Barış, S., Klein, C., Geha, R., Chou, J., Alosaimi, M., Weintraub, L., Boztug, K., Hirschmugl, T., Vilela, M.M.D.S., Holzinger, D., Seidl, M., Lougaris, V., Plebani, A., Alsina, L., Piquer-Gibert, M., Deyà-Martínez, A., Slade, C.A., Aghamohammadi, A., Abolhassani, H., Hammarström, L., Kuismin, O., Helminen, M., Allen, H.L., Thaventhiran, J.E., Freeman, A.F., Cook, M., Bakhtiar, S., Christiansen, M., Cunningham-Rundles, C., Patel, N.C., Rae, W., Niehues, T., Brauer, N., Syrjänen, J., Seppänen, M.R.J., Burns, S.O., Tuijnenburg, P., Kuijpers, T.W., on behalf of NIHR BioResource, Warnatz, K., Grimbacher, B., and NIHR BioResource NIHR BioResource. (2020). Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J. Allergy Clin. Immunol. 146(4): 901–911.
Rojas-Restrepo J., Caballero-Oteyza A., Huebscher K., Haberstroh H., Fliegauf M., Keller B., Kobbe R., Warnatz K., Ehl S., Proietti M., and Grimbacher B. (2021). Establishing the molecular diagnoses in a cohort of 291 patients with predominantly antibody deficiency by targeted next-generation sequencing: Experience from a monocentric study. Front. Immunol. 12: 786516.
Shi C., Wang F., Tong A., Zhang X.-Q., Song H.-M., Liu Z.-Y., Lyu W., Liu Y.-H., and Xia W.-B. (2016). NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: A case report and review of literature. Medicine, 95(40): e5081.
Sun S.-C. (2017). The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol., 17(9): 545–558.
Wirasinha R.C., Davies A.R., Srivastava M., Sheridan J.M., Sng X.Y.X., Delmonte O.M., Dobbs K., Loh K.L., Miosge L.A., Lee C.E., Chand R., Chan A., Yap J.Y., Keller M.D., Chen K., Rossjohn J., La Gruta N.L., Vinuesa C.G., Reid H.H., Lionakis M.S., Notarangelo L.D., Gray D.H.D., Goodnow C.C., Cook M.C., and Daley S.R. (2021). Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility. J. Exp. Med. 218(2): e20200476.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 10 • Number 2 • June 2023
Pages: 30 - 35
History
Received: 7 June 2023
Accepted: 22 June 2023
Accepted manuscript online: 23 June 2023
Version of record online: 18 August 2023
Copyright
© 2023.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
AzharAl Shaqaq and Amarilla B.Mandola. 2023. Novel heterozygous mutation in NFKB2 in a patient with predominantly antibody deficiency. LymphoSign Journal.
10(2): 30-35. https://doi.org/10.14785/lymphosign-2023-0007
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Login options
Check if you access through your login credentials or your institution to get full access on this article.
