A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
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...
Published in: | Nature Communications |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Text |
Language: | English |
Published: |
Nature Publishing Group UK
2018
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Subjects: | |
Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202333/ http://www.ncbi.nlm.nih.gov/pubmed/30361506 https://doi.org/10.1038/s41467-018-06964-x |
Summary: | 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. |
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