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.


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.

MeSH terms

  • Child
  • Colitis / genetics
  • Colitis / pathology
  • Cytochromes b / metabolism
  • Female
  • Granulomatous Disease, Chronic / genetics*
  • Homozygote
  • Humans
  • Loss of Function Mutation / genetics*
  • Male
  • Pedigree
  • Respiratory Burst


  • Cytochromes b