1. Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.
- Author
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Fliegauf, Manfred, L. Bryant, Vanessa, Frede, Natalie, Slade, Charlotte, Woon, See-Tarn, Lehnert, Klaus, Winzer, Sandra, Bulashevska, Alla, Scerri, Thomas, Leung, Euphemia, Jordan, Anthony, Keller, Baerbel, de Vries, Esther, Cao, Hongzhi, Yang, Fang, Schäffer, Alejandro A., Warnatz, Klaus, Browett, Peter, Douglass, Jo, and Ameratunga, Rohan V.
- Subjects
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NF-kappa B , *COMMON variable immunodeficiency , *DISEASE prevalence , *DISEASE relapse , *FRAMESHIFT mutation , *EXONS (Genetics) , *PATIENTS - 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-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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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