Augmentation of STING‐induced type I interferon production in COPA syndrome 

Takashi Kato, Masaki Yamamoto, Yoshitaka Honda, Takashi Orimo, Izumi Sasaki, Kohei Murakami, Hiroaki Hemmi, Yuri Fukuda-Ohta, Kyoichi Isono, Saki Takayama, Hidenori Nakamura, Yoshiro Otsuki, Toshiaki Miyamoto, Junko Takita, Takahiro Yasumi, Ryuta Nishikomori, Tadashi Matsubayashi, Kazushi Izawa, Tsuneyasu Kaisho

Objective
Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene-targeted mouse model.
Methods
We performed whole-exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated.
Results
We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The 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 stimulator of interferon genes (STING)–induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated gene expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production.
Conclusion
V242G, a novel COPA variant, was found in 4 patients from one family. In gene-targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated.

Arthritis & Rheumatology

73

11

2105

2115

10.1002/art.41790