Watkin Levi B, Jessen Birthe, Wiszniewski Wojciech, Vece Timothy J, Jan Max, Sha Youbao, Thamsen Maike, Santos-Cortez Regie L P, Lee Kwanghyuk, Gambin Tomasz, Forbes Lisa R, Law Christopher S, Stray-Pedersen Asbjørg, Cheng Mickie H, Mace Emily M, Anderson Mark S, Liu Dongfang, Tang Ling Fung, Nicholas Sarah K, Nahmod Karen, Makedonas George, Canter Debra L, Kwok Pui-Yan, Hicks John, Jones Kirk D, Penney Samantha, Jhangiani Shalini N, Rosenblum Michael D, Dell Sharon D, Waterfield Michael R, Papa Feroz R, Muzny Donna M, Zaitlen Noah, Leal Suzanne M, Gonzaga-Jauregui Claudia, Boerwinkle Eric, Eissa N Tony, Gibbs Richard A, Lupski James R, Orange Jordan S, Shum Anthony K
1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20.
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 TH17 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.
无偏倚的遗传学研究揭示了人类细胞免疫和自身免疫中令人惊讶的分子机制。我们对五个患有明显孟德尔自身免疫综合征的家族进行了全外显子组测序和靶向测序，该综合征的特征是高滴度自身抗体、炎性关节炎和间质性肺病。我们在COPA基因（编码外被体亚基α）中鉴定出四个独特的有害变体，它们影响相同的功能域。假设突变的COPA通过I型被膜小泡蛋白复合物（COPI）导致细胞内运输缺陷，我们发现COPA变体损害了与靶向高尔基体到内质网逆行运输的蛋白质的结合。此外，突变COPA的表达导致内质网应激以及引发17型辅助性T细胞（TH17）反应的细胞因子上调。患者来源的CD4(+) T细胞也表现出明显偏向TH17表型，这与自身免疫有关。我们的发现揭示了一种囊泡运输蛋白与以肺部和关节疾病为表现的自身免疫综合征之间意想不到的分子联系。
