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COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.
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.
Afiliação
  • Watkin LB; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Jessen B; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Wiszniewski W; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Vece TJ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  • Jan M; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Sha Y; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
  • Thamsen M; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Santos-Cortez RL; Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Lee K; Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Gambin T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Forbes LR; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Law CS; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Stray-Pedersen A; 1] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA. [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Cheng MH; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Mace EM; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Anderson MS; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Liu D; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Tang LF; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
  • Nicholas SK; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Nahmod 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.
  • Makedonas G; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Canter DL; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Kwok PY; 1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
  • Hicks J; Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.
  • Jones KD; Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
  • Penney S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • Rosenblum MD; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
  • Dell SD; Division of Respiratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Waterfield MR; Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
  • Papa FR; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Muzny DM; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • Zaitlen N; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Leal SM; Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Gonzaga-Jauregui C; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Boerwinkle E; 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas, USA.
  • Eissa NT; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
  • Gibbs RA; 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • Lupski JR; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [3] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • Orange JS; 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
  • Shum AK; 1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
Nat Genet ; 47(6): 654-60, 2015 Jun.
Article em En | MEDLINE | ID: mdl-25894502
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 (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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Artrite / Doenças Autoimunes / Doenças Pulmonares Intersticiais / Proteína Coatomer / Complexo de Golgi Tipo de estudo: Prognostic_studies Limite: Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Artrite / Doenças Autoimunes / Doenças Pulmonares Intersticiais / Proteína Coatomer / Complexo de Golgi Tipo de estudo: Prognostic_studies Limite: Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos