{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:45:07Z","timestamp":1782200707919,"version":"3.54.5"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              <jats:italic>MRAS<\/jats:italic>\n              was identified recently as a novel Noonan syndrome (NS)-susceptibility gene. Phenotypically, both patients with NS, harboring pathogenic\n              <jats:italic>MRAS<\/jats:italic>\n              variants, displayed severe cardiac hypertrophy. This study aimed to demonstrate both the necessity and sufficiency of a patient-specific variant (p.Gly23Val-MRAS) to cause NS through the generation and characterization of patient-specific, isogenic control, and disease modeled induced pluripotent stem cell (iPSC) lines.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              iPSCs were derived from a patient with a p.Gly23Val-MRAS variant to assess the effect of\n              <jats:italic>MRAS<\/jats:italic>\n              variants on pathogenesis of NS-associated cardiac hypertrophy. CRISPR\/Cas9 gene editing was used to correct the pathogenic p.Gly23Val-MRAS variant in patient cells (isogenic control) and to introduce the pathogenic variant into unrelated control cells (disease modeled) to determine the necessity and sufficiency of the p.Gly23Val-MRAS variant to elicit the disease phenotype in iPSC-derived cardiomyocytes (iPSC-CMs). iPSC-CMs were analyzed by microscopy and immunofluroesence, single-cell RNAseq, Western blot, room temperature-quantitative polymerase chain reaction, and live-cell calcium imaging to define an in vitro phenotype of\n              <jats:italic>MRAS<\/jats:italic>\n              -mediated cardiac hypertrophy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Compared with controls, both patient and disease modeled iPSC-CMs were significantly larger and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca\n              <jats:sup>2+<\/jats:sup>\n              handling, including increased frequency of irregular Ca\n              <jats:sup>2+<\/jats:sup>\n              transients and changes in Ca\n              <jats:sup>2+<\/jats:sup>\n              handling kinetics.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac hypertrophy phenotype in iPSC-CMs that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling-providing further evidence to establish the monogenetic pathogenicity of p.Gly23Val-MRAS in NS with cardiac hypertrophy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002648","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T19:00:36Z","timestamp":1574190036000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["<i>MRAS<\/i>\n            Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes"],"prefix":"10.1161","volume":"12","author":[{"given":"Erin M.","family":"Higgins","sequence":"first","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Martijn","family":"Bos","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Dotzler","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Mayo Clinic Alix School of Medicine (S.M.D., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CS","family":"John Kim","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Mayo Clinic Alix School of Medicine (S.M.D., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatrics\/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.1080420414"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2009.04.001"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1968.02100020377005"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320210312"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2009-3207"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.67.2.178"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(93)90436-5"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3476(99)70088-0"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91225"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.174287"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.cj-14-0893"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201101100"},{"key":"e_1_3_4_14_2","first-page":"173","article-title":"Role of mitogen-activated protein kinase in cardiac hypertrophy and heart failure.","volume":"8","author":"Zhang W","year":"2003","unstructured":"Zhang, W, et al. 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