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Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20.

COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.

Author information

1
1] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. [2] Texas Children's Hospital Center for Human Immuno-Biology, Houston, Texas, USA.
2
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
5
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
6
Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
7
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.
8
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
9
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.
10
Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.
11
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
12
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
13
Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
14
Division of Respiratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
15
Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
16
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.
17
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.
18
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.
19
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.

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.

PMID:
25894502
PMCID:
PMC4513663
DOI:
10.1038/ng.3279
[Indexed for MEDLINE]
Free PMC Article

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