تقرير
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.
| العنوان: | 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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| المؤلفون: | Aird A; Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile., Lagos M; Clínica Las Condes, Santiago, Chile.; Hospital Padre Hurtado, Santiago, Chile., Vargas-Hernández A; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States., Coban-Akdemir Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States., Jhangiani S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States., Mace EM; Division of Immunogenetics, Department of Pediatrics, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Irving Medical Center, New York, NY, United States., Reyes A; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States., King A; Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile., Cavagnaro F; Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile., Forbes LR; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States., Chinn IK; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States., Lupski JR; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States., Orange JS; Division of Immunogenetics, Department of Pediatrics, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Irving Medical Center, New York, NY, United States., Poli MC; Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.; Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States. |
| المصدر: | Frontiers in pediatrics [Front Pediatr] 2019 Jul 30; Vol. 7, pp. 303. Date of Electronic Publication: 2019 Jul 30 (Print Publication: 2019). |
| نوع المنشور: | Case Reports |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Media SA Country of Publication: Switzerland NLM ID: 101615492 Publication Model: eCollection Cited Medium: Print ISSN: 2296-2360 (Print) Linking ISSN: 22962360 NLM ISO Abbreviation: Front Pediatr Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Lausanne : Frontiers Media SA, [2013]- |
| مستخلص: | 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. |
| References: | Biochem J. 2004 Sep 1;382(Pt 2):393-409. (PMID: 15214841) Eur J Pediatr. 1991 Apr;150(6):400-2. (PMID: 1645668) Pediatr Nephrol. 2006 May;21(5):740-2. (PMID: 16523262) J Clin Invest. 2006 Nov;116(11):2964-71. (PMID: 17039258) J Immunol. 2007 Dec 1;179(11):7514-22. (PMID: 18025196) Mymensingh Med J. 2008 Jul;17(2):210-3. (PMID: 18626461) J Immunol. 2009 Mar 1;182(5):2690-9. (PMID: 19234163) Cell Res. 2011 Jan;21(1):71-85. (PMID: 21173796) J Allergy Clin Immunol. 2011 Jun;127(6):1579-86. (PMID: 21514638) J Clin Endocrinol Metab. 2012 Jan;97(1):E121-8. (PMID: 22013103) Immunol Rev. 2012 Mar;246(1):125-40. (PMID: 22435551) J Korean Med Sci. 2012 Nov;27(11):1436-8. (PMID: 23166431) Eur J Immunol. 2012 Dec;42(12):3141-5. (PMID: 23255011) Am J Hum Genet. 2013 Nov 7;93(5):812-24. (PMID: 24140114) J Clin Immunol. 2014 Aug;34(6):686-90. (PMID: 24888602) Pediatr Nephrol. 2014 Dec;29(12):2325-31. (PMID: 24899237) J Clin Immunol. 2014 Nov;34(8):910-5. (PMID: 25205549) Blood. 2014 Nov 6;124(19):2964-72. (PMID: 25237204) Nat Commun. 2014 Nov 19;5:5360. (PMID: 25406581) BMC Med Genet. 2014 Dec 19;15:139. (PMID: 25524009) J Allergy Clin Immunol. 2015 Jun;135(6):1641-3. (PMID: 25605273) NDT Plus. 2010 Oct;3(5):456-8. (PMID: 25984052) J Immunol. 2015 Aug 1;195(3):953-64. (PMID: 26116508) BMC Nephrol. 2015 Sep 22;16:156. (PMID: 26395882) J Med Genet. 2016 Sep;53(9):575-90. (PMID: 27250108) Haematologica. 2016 Oct;101(10):e392-e396. (PMID: 27365489) Medicine (Baltimore). 2016 Oct;95(40):e5081. (PMID: 27749582) Clin Immunol. 2017 Feb;175:99-108. (PMID: 27923702) Immunobiology. 2017 May;222(5):719-725. (PMID: 28139257) Front Immunol. 2017 Apr 19;8:399. (PMID: 28469620) PLoS One. 2017 Aug 2;12(8):e0181134. (PMID: 28767726) Blood. 2017 Sep 28;130(13):1553-1564. (PMID: 28778864) Clin Rev Allergy Immunol. 2018 Apr;54(2):261-268. (PMID: 29030829) J Allergy Clin Immunol. 2018 Apr;141(4):1479-1482.e6. (PMID: 29225085) J Clin Immunol. 2018 Jan;38(1):129-143. (PMID: 29226301) Immunol Lett. 2018 Feb;194:40-43. (PMID: 29278687) J Immunol. 2018 Apr 1;200(7):2362-2371. (PMID: 29459403) J Dermatol. 2019 Jan;46(1):e24-e26. (PMID: 29952021) Am J Hum Genet. 2018 Aug 2;103(2):171-187. (PMID: 30032986) Immunol Rev. 2019 Jan;287(1):202-225. (PMID: 30565241) |
| معلومات مُعتمدة: | K08 HG008986 United States HG NHGRI NIH HHS; R01 AI120989 United States AI NIAID NIH HHS; R35 NS105078 United States NS NINDS NIH HHS; UM1 HG006542 United States HG NHGRI NIH HHS |
| فهرسة مساهمة: | Keywords: NF-κB2; NK cell deficiency; common variable immunodeficiency (CVID); nephrotic syndrome; pituitary deficiency; primary immunodeficiency; systemic cytomegalovirus |
| تواريخ الأحداث: | Date Created: 20190817 Latest Revision: 20200930 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6682634 |
| DOI: | 10.3389/fped.2019.00303 |
| PMID: | 31417880 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2296-2360 |
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| DOI: | 10.3389/fped.2019.00303 |