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

Gudny A. Arnadottir, Gudmundur L. Norddahl, Steinunn Gudmundsdottir, Arna B. Agustsdottir, Snaevar Sigurdsson, Brynjar O. Jensson, Kristbjorg Bjarnadottir, Fannar Theodors, Stefania Benonisdottir, Erna V. Ivarsdottir, Asmundur Oddsson, Ragnar P. Kristjansson, Gerald Sulem, Kristjan F. Alexandersson, Thorhildur Juliusdottir, Kjartan R. Gudmundsson, Jona Saemundsdottir, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Paolo Manzanillo, Sigurjon A. Gudjonsson, Gudmundur A. Thorisson, Olafur Th. Magnusson, Gisli Masson, Kjartan B. Orvar, Hilma Holm, Sigurdur Bjornsson, Reynir Arngrimsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Asgeir Haraldsson, Patrick Sulem () and Kari Stefansson ()
Additional contact information
Gudny A. Arnadottir: deCODE Genetics/Amgen, Inc.
Gudmundur L. Norddahl: deCODE Genetics/Amgen, Inc.
Steinunn Gudmundsdottir: deCODE Genetics/Amgen, Inc.
Arna B. Agustsdottir: deCODE Genetics/Amgen, Inc.
Snaevar Sigurdsson: deCODE Genetics/Amgen, Inc.
Brynjar O. Jensson: deCODE Genetics/Amgen, Inc.
Kristbjorg Bjarnadottir: deCODE Genetics/Amgen, Inc.
Fannar Theodors: deCODE Genetics/Amgen, Inc.
Stefania Benonisdottir: deCODE Genetics/Amgen, Inc.
Erna V. Ivarsdottir: deCODE Genetics/Amgen, Inc.
Asmundur Oddsson: deCODE Genetics/Amgen, Inc.
Ragnar P. Kristjansson: deCODE Genetics/Amgen, Inc.
Gerald Sulem: deCODE Genetics/Amgen, Inc.
Kristjan F. Alexandersson: deCODE Genetics/Amgen, Inc.
Thorhildur Juliusdottir: deCODE Genetics/Amgen, Inc.
Kjartan R. Gudmundsson: deCODE Genetics/Amgen, Inc.
Jona Saemundsdottir: deCODE Genetics/Amgen, Inc.
Adalbjorg Jonasdottir: deCODE Genetics/Amgen, Inc.
Aslaug Jonasdottir: deCODE Genetics/Amgen, Inc.
Asgeir Sigurdsson: deCODE Genetics/Amgen, Inc.
Paolo Manzanillo: deCODE Genetics/Amgen, Inc.
Sigurjon A. Gudjonsson: deCODE Genetics/Amgen, Inc.
Gudmundur A. Thorisson: deCODE Genetics/Amgen, Inc.
Olafur Th. Magnusson: deCODE Genetics/Amgen, Inc.
Gisli Masson: deCODE Genetics/Amgen, Inc.
Kjartan B. Orvar: Landspitali University Hospital
Hilma Holm: deCODE Genetics/Amgen, Inc.
Sigurdur Bjornsson: Landspitali University Hospital
Reynir Arngrimsson: Landspitali University Hospital
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Ingileif Jonsdottir: deCODE Genetics/Amgen, Inc.
Asgeir Haraldsson: University of Iceland
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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 chip-genotyped 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.

Date: 2018
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DOI: 10.1038/s41467-018-06964-x

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