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Conference Poster Year : 2019

Heterozygous mutations in COPA are associated with enhanced type I interferon signalling

Darragh Duffy
Gillian Rice


Introduction: Heterozygous mutations in COPA, encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy (SAVI). Mutations were originally described to cause endoplasmic reticulum (ER) stress and priming of a T helper 17 response. More recently, increased transcription of interferon (IFN)-stimulated genes (ISGs) was reported in blood circulating cells of affected individuals. However, the precise pathophysiology of this disease remains unclear. Objectives: To better decipher the mechanism of COPA syndrome. Methods: We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in COPA. We assessed type I IFN status by IFNa ultra-sensitive digital quantification in plasma, STAT1 phosphorylation and RNA expression of ISGs in whole blood from patients. In vitro assays also were performed in HEK293T and THP-1 cells to study IFN signalling in the context of COPA mutations. Results: We observed commonalities in the lung pathology between COPA and SAVI, as well as an IFN signature, raised levels of IFNa protein in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model of HEK293T, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids. In THP-1 cells, short hairpin RNA knockdown of COPA induced IFN signalling that was abrogated in the absence of STING. Conclusion: Our data suggest that mutations in COPA lead to constitutive activation of type I IFN signalling through STING. Based on these results, one patient has been treated with the JAK1/2 inhibitor ruxolitinib for the last 12 months. How COPA interacts with ER-resident STING remains to be investigated.


Human genetics
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Dates and versions

inserm-03956476 , version 1 (25-01-2023)


  • HAL Id : inserm-03956476 , version 1


Marie-Louise Frémond, Alice Lepelley, Carolina Uggenti, Maria José Martin-Niclos, Marine Depp, et al.. Heterozygous mutations in COPA are associated with enhanced type I interferon signalling. International Society of Systemic Auto-Inflammatory Diseases, Mar 2019, Genes, Italy. ⟨inserm-03956476⟩
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