{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:38:29Z","timestamp":1790271509065,"version":"4.1.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,5,1]],"date-time":"2014-05-01T00:00:00Z","timestamp":1398902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and \u223c15% of patients with IPAH, their low penetrance (\u223c20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine whether WES can help identify novel gene modifiers in patients with IPAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>A total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual\u2019s risk of developing IPAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201310-1749oc","type":"journal-article","created":{"date-parts":[[2014,4,4]],"date-time":"2014-04-04T10:31:21Z","timestamp":1396607481000},"page":"1260-1272","source":"Crossref","is-referenced-by-count":75,"title":["Whole-Exome Sequencing Reveals\n                    <i>TopBP1<\/i>\n                    as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"189","author":[{"given":"Vinicio A.","family":"de Jesus Perez","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Lyuksyutova","sequence":"additional","affiliation":[{"name":"Texas A&M University, College Station, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Dewey","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"},{"name":"Division of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Orcholski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Shuffle","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Mathur","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"Center for Health Policy and Center for Primary Care and Outcomes Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Luke","family":"Yancy","sequence":"additional","affiliation":[{"name":"Division of Systems Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Rojas","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyun Grace","family":"Li","sequence":"additional","affiliation":[{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"},{"name":"Division of Pediatrics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqin","family":"Cao","sequence":"additional","affiliation":[{"name":"The Vera Moulton Wall Center for Pulmonary Vascular Medicine, and"},{"name":"Stanford Cardiovascular Institute, Stanford University Medical Center, Stanford, California"},{"name":"Division of Pediatrics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tero-Pekka","family":"Alastalo","sequence":"additional","affiliation":[{"name":"Children\\x{2019}s Hospital Helsinki and University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayer","family":"Khazeni","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"Center for Health Policy and Center for Primary Care and Outcomes Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlene A.","family":"Cimprich","sequence":"additional","affiliation":[{"name":"Division of Chemical and Systems Biology, Stanford University, Stanford, California; 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