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

Manfred Fliegauf, Vanessa L Bryant, Natalie Frede, Charlotte Slade, See-Tarn Woon, Klaus Lehnert, Sandra Winzer, Alla Bulashevska, Thomas Scerri, Euphemia Leung, Anthony Jordan, Baerbel Keller, Esther de Vries, Hongzhi Cao, Fang Yang, Alejandro A Schäffer, Klaus Warnatz, Peter Browett, Jo Douglass, Rohan V AmeratungaJos W M van der Meer, Bodo Grimbacher

Research output: Contribution to journalArticleScientificpeer-review

194 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)389-403
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 2015


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