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

被引：75

作者：

Arnadottir, Gudny A. ^{[1
]}

Norddahl, Gudmundur L. ^{[1
]}

Gudmundsdottir, Steinunn ^{[1
]}

Agustsdottir, Arna B. ^{[1
]}

Sigurdsson, Snaevar ^{[1
]}

Jensson, Brynjar O. ^{[1
]}

Bjarnadottir, Kristbjorg ^{[1
]}

Theodors, Fannar ^{[1
]}

Benonisdottir, Stefania ^{[1
]}

Ivarsdottir, Erna V. ^{[1
,2
]}

Oddsson, Asmundur ^{[1
]}

Kristjansson, Ragnar P. ^{[1
]}

Sulem, Gerald ^{[1
]}

Alexandersson, Kristjan F. ^{[1
]}

Juliusdottir, Thorhildur ^{[1
]}

Gudmundsson, Kjartan R. ^{[1
]}

Saemundsdottir, Jona ^{[1
]}

Jonasdottir, Adalbjorg ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Manzanillo, Paolo ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Thorisson, Gudmundur A. ^{[1
]}

Magnusson, Olafur Th. ^{[1
]}

Masson, Gisli ^{[1
]}

Orvar, Kjartan B. ^{[3
,4
]}

Holm, Hilma ^{[1
]}

Bjornsson, Sigurdur ^{[3
,4
]}

Arngrimsson, Reynir ^{[5
,6
]}

Gudbjartsson, Daniel F. ^{[1
,2
]}

Thorsteinsdottir, Unnur ^{[1
,6
]}

Jonsdottir, Ingileif ^{[1
,6
]}

Haraldsson, Asgeir ^{[6
,7
]}

Sulem, Patrick ^{[1
]}

Stefansson, Kari ^{[1
,6
]}

机构：

[1] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[2] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[3] Landspitali Univ Hosp, Dept Internal Med, Reykjavik, Iceland

[4] Glaesibae, Med Ctr, Reykjavik, Iceland

[5] Landspitali Univ Hosp, Dept Genet & Mol Med, Reykjavik, Iceland

[6] Univ Iceland, Fac Med, Reykjavik, Iceland

[7] Childrens Hosp Iceland, Landspitali Univ Hosp, Reykjavik, Iceland

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

INFLAMMATORY-BOWEL-DISEASE; MYCOBACTERIUM-TUBERCULOSIS; LEGIONELLA-PNEUMOPHILA; HUMAN KNOCKOUTS; NADPH OXIDASE; CATALASE; GENE; VARIANTS; PROTEIN; MACROPHAGES;

D O I：

10.1038/s41467-018-06964-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 x 10(-8); OR = 67.6), as well as reduced height (P = 3.3 x 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.

引用

页数：9

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