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Genetics of COPA syndrome

Authors Kumrah R, Mathew B, Vignesh P, Singh S, Rawat A

Received 29 August 2018

Accepted for publication 28 November 2018

Published 8 February 2019 Volume 2019:12 Pages 11—18

DOI https://doi.org/10.2147/TACG.S153600

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Martin H. Maurer


Rajni Kumrah, Babu Mathew, Pandiarajan Vignesh, Surjit Singh, Amit Rawat

Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

Abstract: Inborn errors of immunity usually not only result in immunodeficiency but may also manifest as immune dysregulation in the form of autoinflammation, autoimmunity, or sometimes malignancy. One of the most recently discovered monogenic disorder of immune dysregulation is COPA syndrome. COPA syndrome is an inherited autoimmune disorder caused by mutations in COPA gene. COPA gene encodes for α subunit of the COP1 protein, which is involved in the reverse vesicular protein transport from Golgi apparatus to the endoplasmic reticulum (ER). The inheritance pattern of COPA syndrome is autosomal dominant, and the patients typically present with interstitial lung disease with pulmonary hemorrhage and subsequently develop arthritis. Immunological features involve autoantibody formation, elevated expression of IL-1β and IL-6, and increase in the number of Th17 cells. Molecular pathophysiology of COPA syndrome is not clearly understood. However, it is known that accumulation of unfolded proteins in ER leads to ER stress, which is an indirect result of aberrant vesicular transport of proteins from Golgi apparatus to ER and defective cellular autophagy. ER stress induces inflammation and is responsible for pathogenesis of a large number of chronic inflammatory diseases. Unfolded protein response process responds to improperly folded proteins and defends against stress in ER to ensure the fidelity of the protein folding. It maintains the expression of stress-response genes and causes initiation of inflammatory signaling pathways essential for the innate immunity. Mutation in COPA gene associated with defective protein sorting to ER has unearthed a new primary immunodeficiency disease with a unique clinical phenotype. This review highlights the clinical and molecular aspects of COPA syndrome.

Keywords: COPA syndrome, endoplasmic reticulum stress, autoimmunity, autoinflammation, protein transport, interstitial lung disease, arthritis, Golgi apparatus, interleukins


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