Resolving the polygenic aetiology of a late onset combined immune deficiency caused by NFKB1 haploinsufficiency and modified by PIK3R1 and TNFRSF13B variants
Copyright policy )Resolving the polygenic aetiology of a late onset combined immune deficiency caused by NFKB1 haploinsufficiency and modified by PIK3R1 and TNFRSF13B variants
Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro.
- German Center for Infection Research Germany
- University of Oxford United Kingdom
- Churchill Hospital United Kingdom
- John Radcliffe Hospital United Kingdom
- University of Freiburg Germany
Adult, Male, Adolescent, Transmembrane Activator and CAML Interactor Protein, Immunologic Deficiency Syndromes, 610, NF-kappa B p50 Subunit, Haploinsufficiency, Class Ia Phosphatidylinositol 3-Kinase, Young Adult, Mutation, Humans, Female
Adult, Male, Adolescent, Transmembrane Activator and CAML Interactor Protein, Immunologic Deficiency Syndromes, 610, NF-kappa B p50 Subunit, Haploinsufficiency, Class Ia Phosphatidylinositol 3-Kinase, Young Adult, Mutation, Humans, Female
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).7 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!