Title: | A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease |
Author: |
... 25 more authors Show all authors |
Date: | 2018-10-25 |
Language: | English |
Scope: | 4447 |
University/Institute: | Háskóli Íslands (HÍ) University of Iceland (UI) |
School: | School of Engineering and Natural Sciences (UI) Verkfræði- og náttúruvísindasvið Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) |
Department: | Faculty of Medicine (UI) Læknadeild (HÍ) |
Series: | Nature Communications;9(1) |
ISSN: | 2041-1723 |
DOI: | 10.1038/s41467-018-06964-x |
Subject: | Antimicrobial responses; Disease genetics; Immunological deficiency syndromes; Rare variants; Ónæmisfræði; Erfðafræði |
URI: | https://hdl.handle.net/20.500.11815/1386 |
Citation:Arnadottir, G.A., Norddahl, G.L., Gudmundsdottir, S. et al. A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease. Nat Commun 9, 4447 (2018) doi:10.1038/s41467-018-06964-x
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Abstract:Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are
recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in
humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox)
and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous
loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting
as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst.
Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD)
in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm).
Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct
profile of infections indicative of macrophage dysfunction.
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