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

Gudny A Arnadottir,Kjartan R Gudmundsson,Steinunn Guðmundsdóttir ,Guðmundur Á Þórisson ,Gísli Másson ,Ásgeir Haraldsson ,Ásgeir Sigurðsson ,Kjartan B Örvar ,Stefania Benónísdóttir ,Arna B Agustsdottir ,Ólafur Þ Magnússon ,Fannar Theódórs ,Unnur Þorsteinsdóttir ,Sigurður Björnsson ,Ásmundur Oddsson ,Sigurjon A Gudjonsson,Snævar Sigurdsson ,Gerald Sulem,Reynir Arngrı́msson ,Patrick Sulem,Aðalbjörg Jónasdóttir ,Erna V Ívarsdóttir ,Daníel F Guðbjartsson ,Paolo Manzanillo,Brynjar O Jensson,Jona Saemundsdottir,Thorhildur Juliusdottir,Hilma Hólm ,Kristjan F Alexandersson,Áslaug Jónasdóttir ,Gudmundur L Norddahl,Ingileif Jónsdóttir ,Kristbjörg Bjarnadóttir ,Ragnar P Kristjansson,Kári Stefánsson

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.

Highlights

IntroductionMutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency
The number of infections reported for the brothers was somewhat less than what would be expected in X-linked Chronic granulomatous disease (CGD) patients
No definitive conclusion can be drawn from only one individual, the difference in expression of gp91phox between monocyte-derived macrophages and neutrophils (50% reduced) from homozygous individual D is noteworthy, and suggests the presence of more than one chaperone for cytochrome b-245 in the neutrophil lineage

Summary

Introduction

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. 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. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Genotype-based recall confirms that all eight homozygotes have signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. We show that homozygosity for p.Tyr2Ter results in complete loss of CYBC1, and reduced expression of gp91phox, NADPH oxidase’s main subunit, leading to an impaired oxidative burst.

Methods

Results

Conclusion