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

• Published in: Nature Communications
• Main Authors: Arnadottir, Gudny, Norðdahl, Guðmundur L., Gudmundsdottir, Steinunn, Ágústsdóttir, Arna B., Sigurðsson, Snævar, Jensson, Brynjar Örn, Bjarnadóttir, Kristbjörg, Theodórs, Fannar, Benonisdottir, Stefania, Ívarsdóttir, Erna V., Oddsson, Asmundur, Kristjánsson, Ragnar P., Sulem, Gerald, Alexandersson, Kristján F., Júlíusdóttir, Þórhildur, Guðmundsson, Kjartan R., Sæmundsdóttir, Jóna, Jónasdóttir, Aðalbjörg, Jónasdóttir, Áslaug, Sigurðsson, Ásgeir, Manzanillo, Paolo, Guðjónsson, Sigurjón Axel, Thorisson, Gudmundur A., Magnússon, Ólafur Þ., Másson, Gísli, Örvar, Kjartan B., Holm, Hilma, Björnsson, Sigurður, Arngrimsson, Reynir, Gudbjartsson, Daniel, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Haraldsson, Ásgeir, sulem, patrick, Stefansson, Kari
• Other Authors: Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið, Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands (HÍ), University of Iceland (UI)
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2018
• Subjects: Antimicrobial responses; Disease genetics; Immunological deficiency syndromes; Rare variants; Ónæmisfræði; Erfðafræði; Two Brothers; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/1386; https://doi.org/10.1038/s41467-018-06964-x

Publisher's version (útgefin grein) Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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 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. 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. We wish to thank the family of the two probands, as well as all the other individuals who participated in the study and whose contribution made this work possible. Peer Reviewed