@article{b762d3551f8346708ed035ac788145c3,
title = "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis",
abstract = "Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. 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 α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), 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. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.",
author = "Watkin, {Levi B.} and Birthe Jessen and Wojciech Wiszniewski and Vece, {Timothy J.} and Max Jan and Youbao Sha and Maike Thamsen and Santos-Cortez, {Regie L.P.} and Kwanghyuk Lee and Tomasz Gambin and Forbes, {Lisa R.} and Law, {Christopher S.} and Asbj{\o}rg Stray-Pedersen and Cheng, {Mickie H.} and Mace, {Emily M.} and Anderson, {Mark S.} and Dongfang Liu and Tang, {Ling Fung} and Nicholas, {Sarah K.} and Karen Nahmod and George Makedonas and Canter, {Debra L.} and Kwok, {Pui Yan} and John Hicks and Jones, {Kirk D.} and Samantha Penney and Jhangiani, {Shalini N.} and Rosenblum, {Michael D.} and Dell, {Sharon D.} and Waterfield, {Michael R.} and Papa, {Feroz R.} and Muzny, {Donna M.} and Noah Zaitlen and Leal, {Suzanne M.} and Claudia Gonzaga-Jauregui and Eric Boerwinkle and Eissa, {N. Tony} and Gibbs, {Richard A.} and Lupski, {James R.} and Orange, {Jordan S.} and Shum, {Anthony K.}",
note = "Funding Information: We thank the patients and their families for their involvement in these studies. The group at the University of California San Francisco thanks R. Schekman for useful comments, S. McClymont, O. Estrada, R. Wadia and M. Newasker for assistance with subject recruitment and the University of California San Francisco Genomics Core. Funding was provided by US National Institutes of Health (NIH) grant R01AI067946 (J.S.O.), the Jeffrey Modell Foundation (J.S.O.), US NIH grant K08HL095659 (A.K.S.), the Foundation of the American Thoracic Society (A.K.S.), the Pulmonary Fibrosis Foundation (A.K.S.), the Nina Ireland Lung Disease Program (A.K.S.), US NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute) grant U54HG006542 and (National Institute of Neurological Disorders and Stroke) grant 2RO1NS058529 (J.R.L.), US NIH (National Human Genome Research Institute) grant U54HG003273 (R.A.G.), US NIH grant K23NS078056 (W.W.) and US NIH grant AI053831 (L.B.W.). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = may,
day = "27",
doi = "10.1038/ng.3279",
language = "English (US)",
volume = "47",
pages = "654--660",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",
}