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

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dc.contributor.authorAird, Alejandra
dc.contributor.authorLagos, Macarena
dc.contributor.authorVargas-Hernández, Alexander
dc.contributor.authorPosey, Jennifer
dc.contributor.authorCoban-Akdemir, Zeynep
dc.contributor.authorJhangiani, Shalini
dc.contributor.authorMace, Emily
dc.contributor.authorReyes, Anaid
dc.contributor.authorKing, Alejandra
dc.contributor.authorCavagnaro, Felipe
dc.contributor.authorForbes, Lisa
dc.contributor.authorChinn, Iván
dc.contributor.authorLupski, James
dc.contributor.authorOrange, Jordan
dc.contributor.authorPoli, Cecilia
dc.date.accessioned2019-08-13T20:08:16Z
dc.date.available2019-08-13T20:08:16Z
dc.date.issued2019
dc.description.abstractNuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.
dc.identifier.citationAird A, Lagos M, Vargas-Hernández A, Posey JE, Coban-Akdemir Z, Jhangiani S, Mace EM, Reyes A, King A, Cavagnaro F, Forbes LR, Chinn IK, Lupski JR, Orange JS and Poli MC (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. doi: 10.3389/fped.2019.00303
dc.identifier.urihttp://hdl.handle.net/11447/2575
dc.identifier.uridoi: 10.3389/fped.2019.00303
dc.language.isoen
dc.subjectPrimary immunodeficiency
dc.subjectNF-κB2
dc.subjectCommon variable immunodeficiency (CVID),
dc.subjectNephrotic syndrome
dc.subjectSystemic cytomegalovirus
dc.subjectPituitary deficiency
dc.subjectNK cell deficiency
dc.titleNovel 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
dc.typeArticle

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