Haploinsufficiency of the NF-?B1 Subunit p50 in Common Variable Immunodeficiency.

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-?B pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105?Ex8) is degraded, but is not processed to p50?Ex8. Altered NF-?B1 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-?B1 p50 haploinsufficiency.

SUBMITTER: Fliegauf M 

PROVIDER: S-EPMC4564940 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature