Levi B Watkin, Birthe Jessen, Wojciech Wiszniewski, Timothy J Vece, Max Jan, Youbao Sha, Maike Thamsen, Regie L P 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, Eric Boerwinkle, N Tony Eissa, Richard A Gibbs, James R Lupski, Jordan S Orange, Anthony K Shum
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...
June 2015: Nature Genetics