アカガワ　ヒロユキ   AKAGAWA Hiroyuki   赤川　浩之    所属   研究施設 研究施設    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.
掲載誌名	正式名：Journal of the American Heart Association 略　 称：J Am Heart Assoc ISSNコード：20479980/20479980
掲載区分	国外
巻・号・頁	13(9),pp.e032872
著者・共著者	Ayako Chida-Nagai, Hiroyuki Akagawa, Saori Sawai, Yue-Jiao Ma, Satoshi Yakuwa, Jun Muneuchi, Kazushi Yasuda, Hirokuni Yamazawa, Toshiyuki Yamamoto, Emi Takakuwa, Utano Tomaru, Yoshiyuki Furutani, Tatsuya Kato, Gen Harada, Kei Inai, Toshio Nakanishi, Atsushi Manabe, Atsuhito Takeda, Zhi-Cheng Jing
発行年月	2024/05
概要	BACKGROUND:Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition.METHODS AND RESULTS:We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS.CONCLUSIONS:In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.
DOI	10.1161/JAHA.123.032872
PMID	38639351