Authors
Levi B Watkin, Birthe Jessen, Wojciech Wiszniewski, Timothy J Vece, Max Jan, Youbao Sha, Maike Thamsen, Regie LP Santos-Cortez, Kwanghyuk Lee, Tomasz Gambin, Lisa R Forbes, Christopher S Law, Asbjørg Stray-Pedersen, Mickie H Cheng, Emily M Mace, Mark S Anderson, Dongfang Liu, Ling Fung Tang, Sarah K Nicholas, Karen Nahmod, George Makedonas, Debra L Canter, Pui-Yan Kwok, John Hicks, Kirk D Jones, Samantha Penney, Shalini N Jhangiani, Michael D Rosenblum, Sharon D Dell, Michael R Waterfield, Feroz R Papa, Donna M Muzny, Noah Zaitlen, Suzanne M Leal, Claudia Gonzaga-Jauregui, Baylor-Hopkins Center for Mendelian Genomics, Eric Boerwinkle, N Tony Eissa, Richard A Gibbs, James R Lupski, Jordan S Orange, Anthony K Shum
Publication date
2015/6
Journal
Nature genetics
Volume
47
Issue
6
Pages
654-660
Publisher
Nature Publishing Group US
Description
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 (TH17) response. Patient-derived CD4+ T cells also demonstrate significant skewing toward a TH …
Scholar articles
LB Watkin, B Jessen, W Wiszniewski, TJ Vece, M Jan… - Nature genetics, 2015