Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 May;36(4):377-387.
doi: 10.1007/s10875-016-0271-8. Epub 2016 Apr 5.

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

Timothy J Vece #  1 , Levi B Watkin #  1   2 , Sarah Nicholas  1   2 , Debra Canter  2 , Michael C Braun  1 , R Paul Guillerman  3 , Karen W Eldin  4 , Grant Bertolet  1   2 , Scott McKinley  1 , Marietta de Guzman  1   2 , Lisa Forbes  1   2 , Ivan Chinn  1   2 , Jordan S Orange  1   2
Affiliations
Review

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease

Timothy J Vece et al. J Clin Immunol. 2016 May.

Abstract

Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: "Copa syndrome". Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1β and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.

Keywords: Autoimmunity; arthritis; autosomal dominant; interstitial lung disease; primary immunodeficiency.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Lung imaging findings over time in Copa patients
Serial chest CT images from two patients (A and B) with Copa syndrome. Images initially show ground glass opacities (black arrows) and septal thickening (white arrows) with progression to cysts (red arrows). Figure A1 was at 5 years of age, A2 at 11, and A3 at 14. Figure B1 was at 5 years of age, B2 at 12 years of age, and B3 at 17.
Figure 2
Figure 2. Lung histopathology from Copa syndrome patients
Figures A and B show acute hemorrhage (white arrows) with evidence of chronic hemorrhage with hemosiderin laden macrophages (black arrows). There is also extensive capillaritis noted with neutrophils in the alveolar septa along the pulmonary capillaries(black asterisk). Figures C and D demonstrate acute (white arrow) and chronic (black arrow) pulmonary hemorrhage without capillaritis and increased periairway lymphoid tissue (white asterisk).
Figure 3
Figure 3. MRI imaging of arthritis in Copa syndrome
Figure A shows an MRI of the distal tibia showing osteonecrosis along the right tibial plateau (red arrow), proximal tibia (white arrow), and proximal fibula (black arrow). Figure B shows fatty necrosis along the medial calf, right leg (blue arrow).
Figure 4
Figure 4. “Good Cop, bad Cop” the impact of having a mutant COPA and thus defective COPII complex: A working hypothesis
A) Within healthy controls, in steady state COPI formation and binding of cargo for retrograde transport occurs on the cis-golgi. The COPI vesicle then migrates toward the ER where fusion occurs with the ER membrane allowing for the protein cargo to be delivered. B) Within Copa syndrome COPI formation and migration appears to be normal. However, the binding of protein cargo becomes impaired resulting in a deficit of presumably COPII, amongst other machinery responsible for anterograde protein transport. The cell must then compensate for this deficit by increasing new protein translation resulting in an increase in ER stress. This leads to the release of the protein chaperone BiP from the UPR signaling mediators (PERK, ATF6, IRE1) and their activation. This activation of the UPR results in the activation of PERK resulting in inhibition of elF2 leading to NFκB activation and nuclear translocation. Additionally, the UPR activates ATF6 wich results in increased transcription of XBP1 and further activation of NFκB. Lastly, the UPR activates IRE1 which is responsible for post transcriptional processing of XBP1 transcript. Additionally, be it due to increased ER stress or inappropriate vesicular formation, autophagosomes become excessively large and potentially contribute to increased Inflammasome activation with increased IL-1β processing and secretion.
See this image and copyright information in PMC

Similar articles

  • Genetics of COPA syndrome.
    Kumrah R, Mathew B, Vignesh P, Singh S, Rawat A. Kumrah R, et al. Appl Clin Genet. 2019 Feb 8;12:11-18. doi: 10.2147/TACG.S153600. eCollection 2019. Appl Clin Genet. 2019. PMID: 30804679 Free PMC article. Review.
  • COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.
    Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, Thamsen M, Santos-Cortez RL, Lee K, Gambin T, Forbes LR, Law CS, Stray-Pedersen A, Cheng MH, Mace EM, Anderson MS, Liu D, Tang LF, Nicholas SK, Nahmod K, Makedonas G, Canter DL, Kwok PY, Hicks J, Jones KD, Penney S, Jhangiani SN, Rosenblum MD, Dell SD, Waterfield MR, Papa FR, Muzny DM, Zaitlen N, Leal SM, Gonzaga-Jauregui C; Baylor-Hopkins Center for Mendelian Genomics; Boerwinkle E, Eissa NT, Gibbs RA, Lupski JR, Orange JS, Shum AK. Watkin LB, et al. Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20. Nat Genet. 2015. PMID: 25894502 Free PMC article.
  • An unprecedented COPA gene mutation in two patients in the same family: comparative clinical analysis of newly reported patients with other known COPA gene mutations.
    Patwardhan A, Spencer CH. Patwardhan A, et al. Pediatr Rheumatol Online J. 2019 Aug 27;17(1):59. doi: 10.1186/s12969-019-0359-9. Pediatr Rheumatol Online J. 2019. PMID: 31455335 Free PMC article. Review.
  • COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA.
    Jensson BO, Hansdottir S, Arnadottir GA, Sulem G, Kristjansson RP, Oddsson A, Benonisdottir S, Jonsson H, Helgason A, Saemundsdottir J, Magnusson OT, Masson G, Thorisson GA, Jonasdottir A, Jonasdottir A, Sigurdsson A, Jonsdottir I, Petursdottir V, Kristinsson JR, Gudbjartsson DF, Thorsteinsdottir U, Arngrimsson R, Sulem P, Gudmundsson G, Stefansson K. Jensson BO, et al. BMC Med Genet. 2017 Nov 14;18(1):129. doi: 10.1186/s12881-017-0490-8. BMC Med Genet. 2017. PMID: 29137621 Free PMC article.
  • Imaging findings of COPA Syndrome.
    Nguyen HN, Salman R, Vogel TP, Silva-Carmona M, DeGuzman M, Guillerman RP. Nguyen HN, et al. Pediatr Radiol. 2023 May;53(5):844-853. doi: 10.1007/s00247-023-05600-1. Epub 2023 Feb 7. Pediatr Radiol. 2023. PMID: 36746811
See all similar articles

Cited by

See all "Cited by" articles

References

    1. Picard C, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, et al. J Clin Immunol. Springer; US: 2015. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015; pp. 1–31. - PMC - PubMed
    1. Melki I, Crow YJ. Novel monogenic diseases causing human autoimmunity. Current Opinion in Immunology. 2015;37:1–5. - PubMed
    1. Brown KK. Pulmonary vasculitis. Proc Am Thorac Soc. 2006;3:48–57. - PMC - PubMed
    1. Sacri A-S, Chambaraud T, Ranchin B, Florkin B, Sée H, Decramer S, et al. Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study. Nephrol. Dial. Transplant. 2015;30(Suppl 1):i104–12. - PubMed
    1. Siomou E, Tramma D, Bowen C, Milford DV. Pediatr. Nephrol. Vol. 27. Springer-Verlag; 2012. ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features-outcome; pp. 1911–20. - PubMed

MeSH terms

Substances

LinkOut - more resources