Augmentation of STING-induced type I interferon production in COPA syndrome.

OBJECTIVES COPA syndrome, also known as an autoinflammatory interstitial lung, joint, and kidney (AILJK) disease, is caused by heterozygous mutations in the coatomer subunit alpha (COPA) gene. We found a novel COPA variant in four patients in one family. We aimed to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these four patients and in a gene-targeted mouse model. METHOD We performed whole exome sequencing in seven family members and measured type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and Copa mutant mice we generated. RESULTS We identified a heterozygous variant of COPA gene in the four affected members of the family (c.725T>G, p.Val242Gly). IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G as well as the previously reported disease-causing variants augmented the stimulator of interferon genes (STING)-induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated genes (ISGs) expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated, but hyperactivated upon stimulation and led to increased type I IFN production. CONCLUSION V242G, a novel COPA variant, was found in four patients from one family. The gene-targeted mice with V242G variant recapitulated the interstitial lung disease and showed augmented responses of the STING pathway leading to increase of type I IFN production.