Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency

Fliegauf, M; LBryant V; Frede, N; Slade, C; Woon, ST; Lehnert, K; Winzer, S; Bulashevska, A; Scerri, T; Leung, E; Jordan, A; Keller, B; de Vries, E; Cao, H; Yang, F; Schaffer, AA; Warnatz, K; Browett, P; Douglass, J; Ameratunga, RV; van der Meer, JW; Grimbacher, B

Author(s): Fliegauf, M; LBryant V; Frede, N; Slade, C; Woon, ST; Lehnert, K; Winzer, S; Bulashevska, A; Scerri, T; Leung, E; Jordan, A; Keller, B; de Vries, E; Cao, H; Yang, F; Schaffer, AA; Warnatz, K; Browett, P; Douglass, J; Ameratunga, RV; van der Meer, JW; Grimbacher, B;
Details: Publication Year 2015-08-12,Volume 97,Issue #3,Page 389-403
Journal Title: American Journal of Human Genetics
Publication Type: Journal Article
Abstract: Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In approximately 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-kappaB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105DeltaEx8) is degraded, but is not processed to p50DeltaEx8. Altered NF-kappaB1 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-kappaB1 p50 haploinsufficiency.
Publisher: Cell Press
Research Division(s): Immunology; Population Health And Immunity
PubMed ID: 26279205
Publisher's Version: https://doi.org/10.1016/j.ajhg.2015.07.008
NHMRC Grants: NHMRC/1054925, NHMRC/1075666,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-08-21 12:29:30

Last Modified: 2019-04-01 08:59:44