NDLI: Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Warnatz, Klaus Schäffer, Alejandro A. Cao, Hongzhi Ameratunga, Rohan V. Van Der Meer, Jos W. M. Scerri, Thomas Browett, Peter Leung, Euphemia Jordan, Anthony Grimbacher, Bodo Frede, Natalie de Vries, Esther Woon, See-Tarn Bulashevska, Alla Lehnert, Klaus Winzer, Sandra Bryant, Vanessa L. Slade, Charlotte Yang, Fang Fliegauf, Manfred Keller, Baerbel Douglass, Jo
Spatial Coverage	New Zealand Netherlands Australia
Description	Country affiliation: Germany Author Affiliation: Fliegauf M ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); Bryant VL ( Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia); Frede N ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); Slade C ( Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia); Woon ST ( Department of Virology and Immunology, Auckland City Hospital, Auckland 1023, New Zealand.); Lehnert K ( School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand.); Winzer S ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); Bulashevska A ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); Scerri T ( Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia); Leung E ( Auckland Cancer Society Research Centre and Molecular Medicine and Pathology Department, University of Auckland, Auckland 1142, New Zealand.); Jordan A ( Department of Clinical Immunology, Auckland City Hospital, Auckland 1023, New Zealand.); Keller B ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); de Vries E ( Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch 5200 ME, the Netherlands.); Cao H ( BGI-Shenzhen, Shenzhen, 518083, China.); Yang F ( BGI-Shenzhen, Shenzhen, 518083, China.); Schäffer AA ( NCBI, NIH, Department of Health and Human Services, Bethesda, MD 20894, USA.); Warnatz K ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.); Browett P ( Auckland Cancer Society Research Centre and Molecular Medicine and Pathology Department, University of Auckland, Auckland 1142, New Zealand.); Douglass J ( Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia); Ameratunga RV ( Department of Virology and Immunology, Auckland City Hospital, Auckland 1023, New Zealand.); van der Meer JW ( Department of Internal Medicine, Radboud University Medical Centre, Nijmegen 6525 HP, the Netherlands.); Grimbacher B ( Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany)
Abstract	Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In â ¼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50translated from the non-mutated alleleswere normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.
ISSN	00029297
e-ISSN	15376605
DOI	10.1016/j.ajhg.2015.07.008
Journal	The American Journal of Human Genetics
Issue Number	3
Volume Number	97
Language	English
Publisher	Cell Press (on behalf of American Society of Human Genetics)
Publisher Date	2015-09-03
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Common Variable Immunodeficiency Genetics Haploinsufficiency Nf-kappa B P50 Subunit Blotting, Western Dna Primers Exome Microscopy, Fluorescence Molecular Sequence Data Netherlands New Zealand Sequence Analysis, Dna Multicenter Study Research Support, N.i.h., Intramural Research Support, Non-u.s. Gov't Discipline Human Genetics
Content Type	Text
Resource Type	Article Case study
Subject	Genetics Genetics (clinical)

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