Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency
Fliegauf,Manfred L Bryant,Vanessa Frede,Natalie Slade,Charlotte Woon,See-Tarn Lehnert,Klaus Winzer,Sandra Bulashevska,Alla Scerri,Thomas Leung,Euphemia
Fliegauf,Manfred
L Bryant,Vanessa
Frede,Natalie
Slade,Charlotte
Woon,See-Tarn
Lehnert,Klaus
Winzer,Sandra
Bulashevska,Alla
Scerri,Thomas
Leung,Euphemia
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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Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Date
2015
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Fliegauf, M, L Bryant, V, Frede, N, Slade, C, Woon, S-T, Lehnert, K, Winzer, S, Bulashevska, A, Scerri, T, Leung, E, Jordan, A, Keller, B, de Vries, E, Cao, H, Yang, F, Schäffer, A A, Warnatz, K, Browett, P, Douglass, J, Ameratunga, R V, van der Meer, J W M & Grimbacher, B 2015, 'Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency', American Journal of Human Genetics, vol. 97, no. 3, pp. 389-403. https://doi.org/10.1016/j.ajhg.2015.07.008