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

被引：78

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

共 55 条

[1] Chronic Granulomatous Disease, Catalase, and Actinomyces [J].

Agger, William A. ;

Kowalski, Todd J. .

CLINICAL INFECTIOUS DISEASES, 2010, 50 (09) :1325-1325

[2]

[Anonymous], 2017, DIRECTORATE HLTH

[3] Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters [J].

Arnadottir, Gudny A. ;

Jensson, Brynjar O. ;

Marelsson, Sigurdur E. ;

Sulem, Gerald ;

Oddsson, Asmundur ;

Kristjansson, Ragnar P. ;

Benonisdottir, Stefania ;

Gudjonsson, Sigurjon A. ;

Masson, Gisli ;

Thorisson, Gudmundur A. ;

Saemundsdottir, Jona ;

Magnusson, Olafur Th. ;

Jonasdottir, Adalbjorg ;

Jonasdottir, Aslaug ;

Sigurdsson, Asgeir ;

Gudbjartsson, Daniel F. ;

Thorsteinsdottir, Unnur ;

Arngrimsson, Reynir ;

Sulem, Patrick ;

Stefansson, Kari .

BMC MEDICAL GENETICS, 2017, 18

[4] A Review of Chronic Granulomatous Disease [J].

Arnold, Danielle E. ;

Heimall, Jennifer R. .

ADVANCES IN THERAPY, 2017, 34 (12) :2543-2557

[5] Legionella pneumophila catalase-peroxidases are required for proper trafficking and growth in primary macrophages [J].

Bandyopadhyay, P ;

Byrne, B ;

Chan, Y ;

Swanson, MS ;

Steinman, HM .

INFECTION AND IMMUNITY, 2003, 71 (08) :4526-4535

[6] Epigenetic and genetic components of height regulation [J].

Benonisdottir, Stefania ;

Oddsson, Asmundur ;

Helgason, Agnar ;

Kristjansson, Ragnar P. ;

Sveinbjornsson, Gardar ;

Oskarsdottir, Arna ;

Thorleifsson, Gudmar ;

Davidsson, Olafur B. ;

Arnadottir, Gudny A. ;

Sulem, Gerald ;

Jensson, Brynjar O. ;

Holm, Hilma ;

Alexandersson, Kristjan F. ;

Tryggvadottir, Laufey ;

Walters, G. Bragi ;

Gudjonsson, Sigurjon A. ;

Ward, Lucas D. ;

Sigurdsson, Jon K. ;

Iordache, Paul D. ;

Frigge, Michael L. ;

Rafnar, Thorunn ;

Kong, Augustine ;

Masson, Gisli ;

Helgason, Hannes ;

Thorsteinsdottir, Unnur ;

Gudbjartsson, Daniel F. ;

Sulem, Patrick ;

Stefansson, Kari .

NATURE COMMUNICATIONS, 2016, 7

[7] Genetics of inflammatory bowel disease from multifactorial to monogenic forms [J].

Bianco, Anna Monica ;

Girardelli, Martina ;

Tommasini, Alberto .

WORLD JOURNAL OF GASTROENTEROLOGY, 2015, 21 (43) :12296-12310

[8] Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease [J].

Bustamante, Jacinta ;

Arias, Andres A. ;

Vogt, Guillaume ;

Picard, Capucine ;

Blancas Galicia, Lizbeth ;

Prando, Carolina ;

Grant, Audrey V. ;

Marchal, Christophe C. ;

Hubeau, Marjorie ;

Chapgier, Ariane ;

de Beaucoudrey, Ludovic ;

Puel, Anne ;

Feinberg, Jacqueline ;

Valinetz, Ethan ;

Janniere, Lucile ;

Besse, Celine ;

Boland, Anne ;

Brisseau, Jean-Marie ;

Blanche, Stephane ;

Lortholary, Olivier ;

Fieschi, Claire ;

Emile, Jean-Francois ;

Boisson-Dupuis, Stephanie ;

Al-Muhsen, Saleh ;

Woda, Bruce ;

Newburger, Peter E. ;

Condino-Neto, Antonio ;

Dinauer, Mary C. ;

Abel, Laurent ;

Casanova, Jean-Laurent .

NATURE IMMUNOLOGY, 2011, 12 (03) :213-U47

[9] Host Evasion and Exploitation Schemes of Mycobacterium tuberculosis [J].

Cambier, C. J. ;

Falkow, Stanley ;

Ramakrishnan, Lalita .

CELL, 2014, 159 (07) :1497-1509

[10] Processing and maturation of flavocytochrome b558 include incorporation of heme as a prerequisite for heterodimer assembly [J].

DeLeo, FR ;

Burritt, JB ;

Yu, LX ;

Jesaitis, AJ ;

Dinauer, MC ;

Nauseef, WM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (18) :13986-13993

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