期刊
NATURE GENETICS
卷 47, 期 6, 页码 654-660出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3279
关键词
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资金
- US National Institutes of Health (NIH) grant [R01AI067946]
- Jeffrey Modell Foundation
- US NIH grant [K08HL095659, K23NS078056, AI053831]
- Foundation of the American Thoracic Society
- Pulmonary Fibrosis Foundation
- Nina Ireland Lung Disease Program
- US NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute) grant [U54HG006542]
- (National Institute of Neurological Disorders and Stroke) grant [2RO1NS058529]
- US NIH (National Human Genome Research Institute) grant [U54HG003273]
Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity(1). We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit alpha) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI)(2-4), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (T(H)17) response. Patient-derived CD4(+)T cells also demonstrate significant skewing toward a T(H)17 phenotype that is implicated in autoimmunity(5,6). Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.
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