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A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease


Title: A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Author: Arnadottir, Gudny
Norðdahl, Guðmundur L.
Gudmundsdottir, Steinunn
Ágústsdóttir, Arna B.
Sigurðsson, Snævar
Jensson, Brynjar Örn
Bjarnadóttir, Kristbjörg
Theodórs, Fannar
Benonisdottir, Stefania
Ívarsdóttir, Erna V.
... 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

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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

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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Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.

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