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. Epub 2015 Aug 13.


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.

Publication types

  • Case Reports
  • Multicenter Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Australia
  • Base Sequence
  • Blotting, Western
  • Common Variable Immunodeficiency / genetics*
  • DNA Primers / genetics
  • Exome / genetics
  • Haploinsufficiency / genetics*
  • Humans
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • NF-kappa B p50 Subunit / genetics*
  • Netherlands
  • New Zealand
  • Sequence Analysis, DNA


  • DNA Primers
  • NF-kappa B p50 Subunit