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

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 (gp91 ^phox ) 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.

Abstract

Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.