{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:27:16Z","timestamp":1791296836679,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,10,9]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Bone morphogenic protein receptor 2 (\n              <jats:italic>BMPR2<\/jats:italic>\n              ) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in\n              <jats:italic>BMPR2<\/jats:italic>\n              alternative splicing.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Our data showed that\n              <jats:italic>BMPR2<\/jats:italic>\n              has multiple alternative spliced variants. Two of these, isoform-A (full length) and isoform-B (missing exon 12), were expressed in all tissues analyzed. Analysis of cultured lymphocytes of 47\n              <jats:italic>BMPR2<\/jats:italic>\n              mutation\u2013positive heritable pulmonary arterial hypertension patients and 35\n              <jats:italic>BMPR2<\/jats:italic>\n              mutation\u2013positive unaffected carriers showed that patients had higher levels of isoform-B compared with isoform-A (B\/A ratio) than carriers (\n              <jats:italic>P<\/jats:italic>\n              =0.002). Furthermore, compared with cells with a low B\/A ratio, cells with a high B\/A ratio had lower levels of unphosphorylated cofilin after BMP stimulation. Analysis of exon 12 sequences identified an exonic splice enhancer that binds serine arginine splicing factor 2 (\n              <jats:italic>SRSF2<\/jats:italic>\n              ). Because\n              <jats:italic>SRSF2<\/jats:italic>\n              promotes exon inclusion, reduced\n              <jats:italic>SRSF2<\/jats:italic>\n              expression would mean that exon 12 would not be included in final\n              <jats:italic>BMPR2<\/jats:italic>\n              mRNA (thus promoting increased isoform-B formation). Western blot analysis showed that SRSF2 expression was lower in cells from patients compared with cells from carriers and that siRNA-mediated knockdown of\n              <jats:italic>SRSF2<\/jats:italic>\n              in pulmonary microvascular endothelial cells resulted in elevated levels of isoform-B compared with isoform-A, ie, an elevated B\/A ratio.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Alterations in\n              <jats:italic>BMPR2<\/jats:italic>\n              isoform ratios may provide an explanation of the reduced penetrance among\n              <jats:italic>BMPR2<\/jats:italic>\n              mutation carriers. This ratio is controlled by an exonic splice enhancer in exon 12 and its associated splicing factor, SRSF2.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.112.106245","type":"journal-article","created":{"date-parts":[[2012,8,25]],"date-time":"2012-08-25T03:04:19Z","timestamp":1345863859000},"page":"1907-1916","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":71,"title":["Role of\n            <i>BMPR2<\/i>\n            Alternative Splicing in Heritable Pulmonary Arterial Hypertension Penetrance"],"prefix":"10.1161","volume":"126","author":[{"given":"Joy","family":"Cogan","sequence":"first","affiliation":[{"name":"From the Departments of Pediatrics (J.C., E.A., L.H., B.W., R.H.), Medicine (J.W., J.L.), and Cancer Biology (R.H.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Austin","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (J.C., E.A., L.H., B.W., R.H.), Medicine (J.W., J.L.), and Cancer Biology (R.H.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora","family":"Hedges","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (J.C., E.A., L.H., B.W., R.H.), Medicine (J.W., J.L.), and Cancer Biology (R.H.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Womack","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (J.C., E.A., L.H., B.W., R.H.), Medicine (J.W., J.L.), and Cancer Biology (R.H.), Vanderbilt University Medical Center, Nashville, 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