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 (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.
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Watkin
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Birthe
authors.initials: B
authors.lastname: Jessen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vece
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Jan
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Youbao
authors.initials: Y
authors.lastname: Sha
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Thamsen
authors.affiliation: Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Regie L P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Forbes
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Law
authors.affiliation: 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.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mickie H
authors.initials: MH
authors.lastname: Cheng
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ling Fung
authors.initials: LF
authors.lastname: Tang
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Nicholas
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Nahmod
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: George
authors.initials: G
authors.lastname: Makedonas
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Canter
authors.affiliation: 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.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Penney
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rosenblum
authors.affiliation: Division of Respiratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterfield
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: 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.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Shum
mesh_terms: D000595:Amino Acid Sequence; D001168:Arthritis / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002675:Child, Preschool; D020756:Coatomer Protein / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008126:Lod Score; D017563:Lung Diseases, Interstitial / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D021381:Protein Transport
chemical_list: D020756:Coatomer Protein