{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:43:33Z","timestamp":1791924213082,"version":"4.3.4"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in\n              <jats:italic>KCNK3<\/jats:italic>\n              , was identified as a genetic cause and pharmacological target.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in\n              <jats:italic>ABCC8<\/jats:italic>\n              in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in\n              <jats:italic>ABCC8<\/jats:italic>\n              and identified 11 additional heterozygous predicted damaging\n              <jats:italic>ABCC8<\/jats:italic>\n              variants.\n              <jats:italic>ABCC8<\/jats:italic>\n              encodes SUR1 (sulfonylurea receptor 1)\u2014a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all\n              <jats:italic>ABCC8<\/jats:italic>\n              variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Novel and rare missense variants in\n              <jats:italic>ABCC8<\/jats:italic>\n              are associated with PAH. Identified\n              <jats:italic>ABCC8<\/jats:italic>\n              mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.118.002087","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T09:07:05Z","timestamp":1539335225000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":83,"title":["Loss-of-Function\n            <i>ABCC8<\/i>\n            Mutations in Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"11","author":[{"given":"Michael S.","family":"Bohnen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY."},{"name":"Department of Systems Biology (N.Z., H.Q., Y.S.), Columbia University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjian","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Applied Physics and Applied Mathematics (H.Q., Y.S.), Columbia University, New York, NY."},{"name":"Department of Systems Biology (N.Z., H.Q., Y.S.), Columbia University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor","family":"McClenaghan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology (C.M., C.G.N.) and Center for the Investigation of Membrane Excitability Diseases (C.M., C.G.N.), Washington University School of Medicine, Washington University in St. Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gonzaga-Jauregui","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick E.","family":"Dewey","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Overton","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey G.","family":"Reid","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Shuldiner","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aris","family":"Baras","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bleda","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charaka","family":"Hadinnapola","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Haimel","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.B., C.H., M.H., J.M.M., 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