2. Academic Validation
  3. 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

  • Nat Commun. 2018 Oct 25;9(1):4447. doi: 10.1038/s41467-018-06964-x.
Gudny A Arnadottir 1,  Gudmundur L Norddahl 1,  Steinunn Gudmundsdottir 1,  Arna B Agustsdottir 1,  Snaevar Sigurdsson 1,  Brynjar O Jensson 1,  Kristbjorg Bjarnadottir 1,  Fannar Theodors 1,  Stefania Benonisdottir 1,  Erna V Ivarsdottir 1 2,  Asmundur Oddsson 1,  Ragnar P Kristjansson 1,  Gerald Sulem 1,  Kristjan F Alexandersson 1,  Thorhildur Juliusdottir 1,  Kjartan R Gudmundsson 1,  Jona Saemundsdottir 1,  Adalbjorg Jonasdottir 1,  Aslaug Jonasdottir 1,  Asgeir Sigurdsson 1,  Paolo Manzanillo 1,  Sigurjon A Gudjonsson 1,  Gudmundur A Thorisson 1,  Olafur Th Magnusson 1,  Gisli Masson 1,  Kjartan B Orvar 3 4,  Hilma Holm 1,  Sigurdur Bjornsson 3 4,  Reynir Arngrimsson 5 6,  Daniel F Gudbjartsson 1 2,  Unnur Thorsteinsdottir 1 6,  Ingileif Jonsdottir 1 6,  Asgeir Haraldsson 6 7,  Patrick Sulem 8,  Kari Stefansson 9 10
Affiliations

Affiliations

  • 1 deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • 2 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
  • 3 Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
  • 4 The Medical Center, Glaesibae, Reykjavik, Iceland.
  • 5 Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland.
  • 6 Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • 7 Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland.
  • 8 deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. patrick.sulem@decode.is.
  • 9 deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. kari.stefansson@decode.is.
  • 10 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kari.stefansson@decode.is.
PMID: 30361506 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 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.

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