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
  • 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. [email protected].
  • 9. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [email protected].
  • 10. Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [email protected].
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.