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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.author Aird, Alejandra
dc.contributor.author Lagos, Macarena
dc.contributor.author Vargas-Hernández, Alexander
dc.contributor.author Posey, Jennifer
dc.contributor.author Coban-Akdemir, Zeynep
dc.contributor.author Jhangiani, Shalini
dc.contributor.author Mace, Emily
dc.contributor.author Reyes, Anaid
dc.contributor.author King, Alejandra
dc.contributor.author Cavagnaro, Felipe
dc.contributor.author Forbes, Lisa
dc.contributor.author Chinn, Iván
dc.contributor.author Lupski, James
dc.contributor.author Orange, Jordan
dc.contributor.author Poli, María Cecilia
dc.date.accessioned 2019-08-13T20:08:16Z
dc.date.available 2019-08-13T20:08:16Z
dc.date.issued 2019
dc.identifier.citation Aird 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.uri http://hdl.handle.net/11447/2575
dc.identifier.uri doi: 10.3389/fped.2019.00303
dc.description.abstract Nuclear 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.language.iso en
dc.subject Primary immunodeficiency
dc.subject NF-κB2
dc.subject Common variable immunodeficiency (CVID),
dc.subject Nephrotic syndrome
dc.subject Systemic cytomegalovirus
dc.subject Pituitary deficiency
dc.subject NK cell deficiency
dc.title 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
dc.type Article


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