{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T12:02:45Z","timestamp":1780056165386,"version":"3.54.0"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,5,7]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              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\u2010to\u2010severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole\u2010exome sequencing identified a rare\n              <jats:italic>PTGIS<\/jats:italic>\n              nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I\n              <jats:sub>2<\/jats:sub>\n              synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the\n              <jats:italic>PTGIS<\/jats:italic>\n              p.E314X variant\u2010encoding construct when compared with that in cells transfected with the wild\u2010type\n              <jats:italic>PTGIS<\/jats:italic>\n              \u2010encoding 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 I\n              <jats:sub>2<\/jats:sub>\n              synthase levels and urinary prostaglandin I metabolite levels. We identified another\n              <jats:italic>PTGIS<\/jats:italic>\n              rare splice\u2010site variant (c.1358+2T&gt;C) in another pediatric patient with WS and severe PPS.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              In total, 2 rare nonsense\/splice\u2010site\n              <jats:italic>PTGIS<\/jats:italic>\n              variants were identified in 2 pediatric patients with WS and severe PPS.\n              <jats:italic>PTGIS<\/jats:italic>\n              variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.032872","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T11:15:27Z","timestamp":1713525327000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of\n            <i>\n              Prostaglandin I\n              <sub>2<\/sub>\n              Synthase\n            <\/i>\n            Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1277-6119","authenticated-orcid":false,"given":"Ayako","family":"Chida\u2010Nagai","sequence":"first","affiliation":[{"name":"Department of Pediatrics Hokkaido University Hospital Sapporo Japan"},{"name":"Department of Pediatric Cardiology and Adult Congenital Cardiology Tokyo Women\u2019s Medical University Tokyo 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