{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:55:28Z","timestamp":1792108528352,"version":"4.4.0"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,9,15]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS\u2013mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (\n              <jats:italic>LZTR1<\/jats:italic>\n              ). We generated induced pluripotent stem cell\u2013derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Patients\u2019 induced pluripotent stem cell\u2013derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS\u2013mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell\u2013derived cardiomyocytes from NS patients carrying biallelic variants in\n              <jats:italic>LZTR1<\/jats:italic>\n              and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044794","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T09:00:14Z","timestamp":1594026014000},"page":"1059-1076","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":71,"title":["Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome\u2013Associated Cardiomyopathy"],"prefix":"10.1161","volume":"142","author":[{"given":"Ulrich","family":"Hanses","sequence":"first","affiliation":[{"name":"Clinic for Cardiology and Pneumology (U.H., M.K., L.R., R.H., G.H., L.C.)"},{"name":"DZHK (German Center for Cardiovascular Research), partner site G\u00f6ttingen, Mannheim and Berlin, Germany (U.H., M.K., L.R., G.Y., B.B., I.E-B., M.T., R.H., S.D., T.P., W.-H.Z., G.H., B.W., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Kleinsorge","sequence":"additional","affiliation":[{"name":"Clinic for Cardiology and Pneumology (U.H., M.K., L.R., R.H., G.H., L.C.)"},{"name":"DZHK (German Center for Cardiovascular Research), partner site G\u00f6ttingen, Mannheim and Berlin, Germany (U.H., M.K., L.R., G.Y., B.B., I.E-B., M.T., R.H., S.D., T.P., W.-H.Z., G.H., B.W., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Roos","sequence":"additional","affiliation":[{"name":"Clinic for Cardiology and Pneumology (U.H., M.K., L.R., R.H., G.H., L.C.)"},{"name":"DZHK (German Center for Cardiovascular Research), partner site G\u00f6ttingen, Mannheim and Berlin, Germany (U.H., M.K., L.R., G.Y., B.B., I.E-B., M.T., R.H., S.D., T.P., W.-H.Z., G.H., B.W., 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