A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
| Autor: | Kjartan R Gudmundsson, Olafur Th Magnusson, Thorhildur Juliusdottir, Unnur Thorsteinsdottir, Jona Saemundsdottir, Ásgeir Haraldsson, Gisli Masson, Steinunn Gudmundsdottir, Aslaug Jonasdottir, Erna V. Ivarsdottir, Sigurdur Bjornsson, Adalbjorg Jonasdottir, Gudmundur A. Thorisson, Daniel F. Gudbjartsson, Asmundur Oddsson, Kari Stefansson, Sigurjon A. Gudjonsson, Gudmundur L. Norddahl, Kristjan F. Alexandersson, Snaevar Sigurdsson, Ragnar P. Kristjansson, Hilma Holm, Brynjar O. Jensson, Gerald Sulem, Kjartan B. Orvar, Gudny A. Arnadottir, Asgeir Sigurdsson, Arna B Agustsdottir, Kristbjorg Bjarnadottir, Fannar Theodors, Patrick Sulem, Paolo Manzanillo, Stefania Benonisdottir, Ingileif Jonsdottir, Reynir Arngrímsson |
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| Přispěvatelé: | 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) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male congenital hereditary and neonatal diseases and abnormalities Science General Physics and Astronomy Granulomatous Disease Chronic Inflammatory bowel disease General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Chronic granulomatous disease Immunological deficiency syndromes NADPH oxidase complex Loss of Function Mutation immune system diseases hemic and lymphatic diseases medicine Erfðafræði Humans Colitis lcsh:Science Child Ónæmisfræði Respiratory Burst Oxidase test Multidisciplinary NADPH oxidase biology business.industry Disease genetics Homozygote Rare variants General Chemistry Antimicrobial responses Cytochromes b medicine.disease Respiratory burst Pedigree 030104 developmental biology 030220 oncology & carcinogenesis Immunology biology.protein Primary immunodeficiency lcsh:Q Female business |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-9 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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