Augmentation of Stimulator of Interferon Genes–Induced Type I Interferon Production in COPA Syndrome

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...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2021-11, Vol.73 (11), p.2105-2115
Main Authors: Kato, Takashi, Yamamoto, Masaki, Honda, Yoshitaka, Orimo, Takashi, Sasaki, Izumi, Murakami, Kohei, Hemmi, Hiroaki, Fukuda‐Ohta, Yuri, Isono, Kyoichi, Takayama, Saki, Nakamura, Hidenori, Otsuki, Yoshiro, Miyamoto, Toshiaki, Takita, Junko, Yasumi, Takahiro, Nishikomori, Ryuta, Matsubayashi, Tadashi, Izawa, Kazushi, Kaisho, Tsuneyasu
Format: Article
Language:English
Subjects:
Alleles
Blood cells
Coatomer Protein - genetics
Dendritic cells
DNA Mutational Analysis
Female
Gene expression
Genes
Heterozygote
Humans
Interferon
Interferon Type I - genetics
Joint Diseases - genetics
Joint Diseases - immunology
Kidney diseases
Kidney Diseases - genetics
Kidney Diseases - immunology
Lung diseases
Lung Diseases, Interstitial - genetics
Lung Diseases, Interstitial - immunology
Male
Mutation
Mutation, Missense
Pedigree
Peripheral blood
Stimulators
Whole Exome Sequencing
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Summary: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.
ISSN:2326-5191
2326-5205
DOI:10.1002/art.41790