ArticleThe Journal of clinical investigation2011
Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 172 papers, 1 of them a synthesis that pooled it.
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Who cites it
172 citing papers in PubMed, 1 synthesis or guideline pooled it, 274 citations in OpenAlex.
- Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.Circulation. Genomic and precision medicine · 2024Pooled it
- Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial.Circulation. Heart failure · 2025Trial
- Rigosertib Reverses Hypertrophic Cardiomyopathy in Noonan Syndrome.Circulation · 2026Article
- Targeting Interleukin-8-Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome.Circulation · 2026Article
- In Silico Discovery of mTOR Inhibitors as Potential Therapeutics for Feline Hypertrophic Cardiomyopathy.Journal of molecular modeling · 2026Article
- Largely preserved vestibular function despite severe-to-profound hearing loss in Noonan syndrome spectrum disorders.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2026Article
- Promoting Autophagy Mitigates Stress-Induced Remodeling in Patient iPSC-CMs with the Phospholamban R9C Mutation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Deregulation of m6A-RNA methylation impairs adaptive hypertrophic response and drives maladaptation via mTORC1-S6K1-hyperactivation and autophagy impairment.Cell communication and signaling : CCS · 2025Article
- Mechanism of RNA Oxidation and Its Inhibitor Involved in Ang II-Induced Cardiomyocyte Hypertrophy.Aging medicine (Milton (N.S.W)) · 2025Article
- Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.Molecular autism · 2025Article
- SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR-IRX transcription factor signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices.ESC heart failure · 2025Article
- Cardiovascular aspects of Noonan syndrome and related disorders.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Comprehensive Plasma Proteomic Profiling Reveals Differentially Regulated Signaling Pathways Underlying Left Ventricular Hypertrophy Between Hypertrophic Cardiomyopathy and Aortic Stenosis.Journal of cardiovascular translational research · 2025Article
- PTPN11 in cartilage development, adult homeostasis, and diseases.Bone research · 2025Review
- Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy.JACC. Basic to translational science · 2025Article
- Adaptor protein Src-homology 2 domain containing E (SH2E) deficiency induces heart defect in zebrafish.Acta pharmacologica Sinica · 2025Article
- Case Report: A rare case of Noonan syndrome with multiple lentigines manifesting as cardiac enlargement.Frontiers in cardiovascular medicine · 2025Article
- Baicalin improves isoproterenol-induced cardiac remodeling by regulating the Nrf2-dependent signaling pathway.BMC cardiovascular disorders · 2024Article
112 more citing papers are in PubMed but not listed here.
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14 authors at 7 institutions in 4 countries.
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Abstract
LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.