Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity1. 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)2,3,4, 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 autoimmunity5,6. 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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We thank the patients and their families for their involvement in these studies. The group at the University of California San Francisco thanks R. Schekman for useful comments, S. McClymont, O. Estrada, R. Wadia and M. Newasker for assistance with subject recruitment and the University of California San Francisco Genomics Core. Funding was provided by US National Institutes of Health (NIH) grant R01AI067946 (J.S.O.), the Jeffrey Modell Foundation (J.S.O.), US NIH grant K08HL095659 (A.K.S.), the Foundation of the American Thoracic Society (A.K.S.), the Pulmonary Fibrosis Foundation (A.K.S.), the Nina Ireland Lung Disease Program (A.K.S.), US NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute) grant U54HG006542 and (National Institute of Neurological Disorders and Stroke) grant 2RO1NS058529 (J.R.L.), US NIH (National Human Genome Research Institute) grant U54HG003273 (R.A.G.), US NIH grant K23NS078056 (W.W.) and US NIH grant AI053831 (L.B.W.).

Author information

Author notes

    • Levi B Watkin
    • , Birthe Jessen
    •  & Wojciech Wiszniewski

    These authors contributed equally to this work.

    • James R Lupski
    • , Jordan S Orange
    •  & Anthony K Shum

    These authors jointly supervised this work.


  1. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

    • Levi B Watkin
    • , Timothy J Vece
    • , Lisa R Forbes
    • , Emily M Mace
    • , Dongfang Liu
    • , Sarah K Nicholas
    • , Karen Nahmod
    • , George Makedonas
    • , Debra L Canter
    • , James R Lupski
    •  & Jordan S Orange
  2. Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.

    • Levi B Watkin
    • , Lisa R Forbes
    • , Asbjørg Stray-Pedersen
    • , Emily M Mace
    • , Dongfang Liu
    • , Sarah K Nicholas
    • , Karen Nahmod
    • , George Makedonas
    • , Debra L Canter
    •  & Jordan S Orange
  3. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Birthe Jessen
    • , Max Jan
    • , Maike Thamsen
    • , Christopher S Law
    • , Mickie H Cheng
    • , Mark S Anderson
    • , Feroz R Papa
    • , Noah Zaitlen
    •  & Anthony K Shum
  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Wojciech Wiszniewski
    • , Tomasz Gambin
    • , Asbjørg Stray-Pedersen
    • , Samantha Penney
    • , Claudia Gonzaga-Jauregui
    • , Richard A Gibbs
    •  & James R Lupski
  5. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

    • Youbao Sha
    •  & N Tony Eissa
  6. Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Regie L P Santos-Cortez
    • , Kwanghyuk Lee
    •  & Suzanne M Leal
  7. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.

    • Ling Fung Tang
    • , Pui-Yan Kwok
    •  & Anthony K Shum
  8. Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.

    • Pui-Yan Kwok
    •  & Michael D Rosenblum
  9. Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.

    • John Hicks
  10. Department of Pathology, University of California, San Francisco, San Francisco, California, USA.

    • Kirk D Jones
  11. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Shalini N Jhangiani
    • , Donna M Muzny
    • , Eric Boerwinkle
    • , Richard A Gibbs
    •  & James R Lupski
  12. Division of Respiratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Sharon D Dell
  13. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.

    • Michael R Waterfield
  14. Human Genetics Center and Institute of Molecular Medicine, University of Texas–Houston Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle


  1. Baylor-Hopkins Center for Mendelian Genomics

    Houston, Texas, USA.


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L.B.W., B.J. and W.W. designed and performed experiments, analyzed data and wrote the manuscript. T.J.V., L.R.F., D.L.C., S.K.N., S.D.D. and M.R.W. provided clinical care and analyzed clinical data. J.H. and K.D.J. performed pathology services. A.S.-P., K.L., T.G., R.L.P.S.-C., C.-G.J., N.Z. and L.F.T. analyzed data. Y.S., E.M.M., D.L., K.N., M.T., M.J. and C.S.L. performed experiments and analyzed data. G.M., N.T.E., F.R.P. and M.D.R. designed experiments and analyzed data. S.N.J., S.P., D.M.M., E.B., R.A.G., M.S.A. and P.-Y.K. organized studies. S.M.L., R.L.P.S.-C. and M.H.C. analyzed data and assisted with writing the manuscript. J.S.O., J.R.L. and A.K.S. supervised the study and wrote the manuscript.

Competing interests

J.R.L. has stock ownership in 23 and Me, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in the Baylor Miraca Genetics Laboratory (BMGL). R.A.G. is an advisor to GE Healthcare/Clarient, Inc. and the Allen Institute for Brain Science and is interim CSO of the BMGL. The other authors have no disclosures relevant to the manuscript.

Corresponding authors

Correspondence to Jordan S Orange or Anthony K Shum.

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