Novel Heterozygous Mutation in Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome.

 
TitleNovel Heterozygous Mutation in Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome.
Publication TypeJournal Article
Year of Publication2019
AuthorsAird, A, Lagos, M, Vargas-Hernandez, A, Posey, JE, Coban-Akdemir, Z, Jhangiani, S, Mace, EM, Reyes, A, King, A, Cavagnaro, F, Forbes, LR, Chinn, IK, Lupski, JR, Orange, JS, Poli, MCecilia
JournalFront Pediatr
Volume7
Pagination303
Date Published2019
ISSN2296-2360
Abstract

Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by (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 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 heterozygous nonsense mutation in (c.2611C>T, p.Gln871) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be 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.

DOI10.3389/fped.2019.00303
Alternate JournalFront Pediatr
PubMed ID31417880
PubMed Central IDPMC6682634
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States