deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Nat Commun. 2018 Oct 25;9(1):4447. doi: 10.1038/s41467-018-06964-x.
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) 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; OR = 67.6), as well as reduced height (P = 3.3 × 10; -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.
吞噬细胞 NADPH 氧化酶复合物亚基编码基因突变可导致慢性肉芽肿病（CGD），这是一种严重的原发性免疫缺陷病。本文描述了人类中一种先前未被表征的蛋白 CYBC1（C17orf62）缺失如何导致 NADPH 氧化酶主要亚基（gp91）表达减少，并导致 CGD。通过分析两名被诊断为 CGD 的兄弟，我们在 CYBC1 中发现了一个纯合无功能突变 p.Tyr2Ter。将 p.Tyr2Ter 代入 155K 芯片基因分型的冰岛人群中，发现了另外 6 个纯合子，均有 CGD 的迹象，表现为结肠炎、罕见感染或严重的 PMA 诱导中性粒细胞氧化爆发受损。因此，p.Tyr2Ter 的纯合性与冰岛的炎症性肠病（IBD）相关（P=8.3×10；OR=67.6），以及身高降低相关（P=3.3×10；-8.5cm）。总之，我们发现 CYBC1 缺乏会导致 CGD，其特征为结肠炎和特定的感染模式，提示巨噬细胞功能障碍。
