Haploinsufficiency of the NF-kappaB1 Subunit p50 in Common Variable Immunodeficiency
SourceAmerican Journal of Human Genetics, 97, 3, (2015), pp. 389-403
Article / Letter to editor
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American Journal of Human Genetics
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
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.
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