{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:45:13Z","timestamp":1792676713463,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      (encoding BMP9) variants have been described in pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT), as well as a few\n                      <jats:italic toggle=\"yes\">BMP10<\/jats:italic>\n                      variants in PAH. The purpose of the present study was to develop a functional assay capable of discriminating benign from pathogenic variants and to characterize the underlying molecular mechanisms responsible for their loss of function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We developed a single-step functional assay in which C2C12 cells stably expressing a BMP (bone morphogenetic protein)-responsive element upstream of a firefly luciferase reporter would be stimulated by the autocrine secretion of BMP9 or BMP10 variants produced by transfected expression plasmids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Using this functional assay, we reclassified all\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      variants and 2 out of 5\n                      <jats:italic toggle=\"yes\">BMP10<\/jats:italic>\n                      variants identified in patients with PAH as likely pathogenic. In contrast, only 2 of the 4\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      variants identified in suspected patients with HHT were found to be likely pathogenic; nevertheless, none of the patients met the diagnostic criteria for hereditary hemorrhagic telangiectasia. We also showed, using ELISAs and Western blots, that the loss of function of\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">BMP10<\/jats:italic>\n                      variants was mostly due to altered processing (folding\/stability defects). Moreover, we found that loss-of-function\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      variants impaired the secretion of BMP10, suggesting a potential dominant-negative mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      We developed a functional assay for\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">BMP10<\/jats:italic>\n                      variants, enabling the reclassification of variants of unknown significance. Together, this study further supports the involvement of\n                      <jats:italic toggle=\"yes\">GDF2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">BMP10<\/jats:italic>\n                      as predisposing genes in PAH. This single-step assay will be transferable to clinical genetic laboratories and will improve diagnosis of patients with PAH and HHT.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005626","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:00:54Z","timestamp":1780995654000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Functional and Molecular Characterization of Novel\n                    <i>GDF2<\/i>\n                    (\n                    <i>BMP9<\/i>\n                    ) and\n                    <i>BMP10<\/i>\n                    Variants From the French PAH and HHT Cohorts"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-9504","authenticated-orcid":true,"given":"Agn\u00e8s","family":"Desroches-Castan","sequence":"first","affiliation":[{"name":"Biosant\u00e9 unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France (A.D.-C., L.B.-S., V.A., E.T., S.D.-G., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1575-7510","authenticated-orcid":true,"given":"L\u00e9a","family":"Beurier-Soulat","sequence":"additional","affiliation":[{"name":"Biosant\u00e9 unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France (A.D.-C., L.B.-S., V.A., E.T., S.D.-G., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2699-3827","authenticated-orcid":true,"given":"Maud","family":"Tusseau","sequence":"additional","affiliation":[{"name":"Hospices Civils de Lyon, National HHT Reference Center and Genetics Department, Bron, France (M.T., S.G., G.L., A.G., S.D.-G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5325-5272","authenticated-orcid":true,"given":"Florence","family":"Coulet","sequence":"additional","affiliation":[{"name":"Sorbonne University, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Medical Genetics Department, APHP, Paris, France (F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8788-1450","authenticated-orcid":true,"given":"Valentin","family":"Azemard","sequence":"additional","affiliation":[{"name":"Biosant\u00e9 unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France (A.D.-C., L.B.-S., V.A., E.T., S.D.-G., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2052-9425","authenticated-orcid":true,"given":"Delphine","family":"Logeart-Avramoglou","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, CNRS, Inserm, B3OA, Paris, France 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