{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:44:58Z","timestamp":1790811898830,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,7,16]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      More than 90% of individuals with Noonan syndrome (NS) with mutations clustered in the CR2 domain of\n                      <jats:italic>RAF1<\/jats:italic>\n                      present with severe and often lethal hypertrophic cardiomyopathy (HCM). The signaling pathways by which NS\n                      <jats:italic>RAF1<\/jats:italic>\n                      mutations promote HCM remain elusive, and so far, there is no known treatment for NS-associated HCM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We used patient-derived\n                      <jats:italic>\n                        RAF1\n                        <jats:sup>S257L\/+<\/jats:sup>\n                      <\/jats:italic>\n                      and CRISPR-Cas9\u2013generated isogenic control inducible pluripotent stem cell (iPSC)\u2013derived cardiomyocytes to model NS\n                      <jats:italic>RAF1<\/jats:italic>\n                      -associated HCM and to further delineate the molecular mechanisms underlying the disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We show that mutant iPSC\u2013derived cardiomyocytes phenocopy the pathology seen in hearts of patients with NS by exhibiting hypertrophy and structural defects. Through pharmacological and genetic targeting, we identify 2 perturbed concomitant pathways that, together, mediate HCM in\n                      <jats:italic>RAF1<\/jats:italic>\n                      mutant iPSC\u2013derived cardiomyocytes. Hyperactivation of mitogen-activated protein kinase kinase 1\/2 (MEK1\/2), but not extracellular regulated kinase 1\/2, causes myofibrillar disarray, whereas the enlarged cardiomyocyte phenotype is a direct consequence of increased extracellular regulated kinase 5 (ERK5) signaling, a pathway not previously known to be involved in NS. RNA-sequencing reveals genes with abnormal expression in\n                      <jats:italic>RAF1<\/jats:italic>\n                      mutant iPSC\u2013derived cardiomyocytes and identifies subsets of genes dysregulated by aberrant MEK1\/2 or ERK5 pathways that could contribute to the NS-associated HCM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Taken together, the results of our study identify the molecular mechanisms by which NS\n                      <jats:italic>RAF1<\/jats:italic>\n                      mutations cause HCM and reveal downstream effectors that could serve as therapeutic targets for treatment of NS and perhaps other, more common, congenital HCM disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.037227","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T05:00:17Z","timestamp":1559710817000},"page":"207-224","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":74,"title":["Inducible Pluripotent Stem Cell\u2013Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1\/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in\n                    <i>RAF1<\/i>\n                    -Associated Noonan Syndrome"],"prefix":"10.1161","volume":"140","author":[{"given":"Fabrice","family":"Jaffr\u00e9","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (F.J., M.I.K.)"},{"name":"Harvard Medical School, Boston, MA (F.J., M.I.K.)."},{"name":"Department of Surgery, Weill Cornell Medical College, New York, NY (F.J., 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