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

Am J Hum Genet. 2015 Sep 3;97(3):389-403. doi: 10.1016/j.ajhg.2015.07.008.

Manfred Fliegauf ¹, Vanessa L Bryant ², Natalie Frede ¹, Charlotte Slade ³, See-Tarn Woon ⁴, Klaus Lehnert ⁵, Sandra Winzer ¹, Alla Bulashevska ¹, Thomas Scerri ², Euphemia Leung ⁶, Anthony Jordan ⁷, Baerbel Keller ¹, Esther de Vries ⁸, Hongzhi Cao ⁹, Fang Yang ⁹, Alejandro A Schäffer ¹⁰, Klaus Warnatz ¹, Peter Browett ⁶, Jo Douglass ¹¹, Rohan V Ameratunga ⁴, Jos W M van der Meer ¹², Bodo Grimbacher ¹³

Affiliations

1 Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
2 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
3 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
4 Department of Virology and Immunology, Auckland City Hospital, Auckland 1023, New Zealand.
5 School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand.
6 Auckland Cancer Society Research Centre and Molecular Medicine and Pathology Department, University of Auckland, Auckland 1142, New Zealand.
7 Department of Clinical Immunology, Auckland City Hospital, Auckland 1023, New Zealand.
8 Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch 5200 ME, the Netherlands.
9 BGI-Shenzhen, Shenzhen, 518083, China.
10 NCBI, NIH, Department of Health and Human Services, Bethesda, MD 20894, USA.
11 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
12 Department of Internal Medicine, Radboud University Medical Centre, Nijmegen 6525 HP, the Netherlands.
13 Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany; Institute of Immunity and Transplantation, University College London, London WC1E 6BT, UK. Electronic address: [email protected].

PMID: 26279205 DOI: 10.1016/j.ajhg.2015.07.008

Abstract

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% 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 p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

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