ArticleCirculation2019
Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome.
Article in Circulation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 67 citations in OpenAlex.
- 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
- Novel Use of Mavacamten in RAF1-Associated Noonan Syndrome With Hypertrophic Cardiomyopathy.JACC. Case reports · 2026Article
- Berberine Attenuates Hypertrophic Phenotype in RAF1-Mutant Induced Pluripotent Stem Cell-Derived Cardiomyocytes through Suppression of ERK5-Cyclin D1 Signaling.Cardiovascular drugs and therapy · 2026Article
- In Vitro Modelling of Obstructive Sleep Apnea by Intermittent Hypoxia of Human Embryonic Stem Cell-Derived Cardiomyocytes: Expression of ERK1/2, ERK5 and Erbin.International journal of molecular sciences · 2026Article
- Huayu-qutan formula ameliorates hypertrophic cardiomyopathy by regulating MAPK and HIF‑1α-signaling pathways.Chinese medicine · 2026Article
- Cardiovascular aspects of Noonan syndrome and related disorders.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices.ESC heart failure · 2025Article
- Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy.International journal of molecular sciences · 2025Review
- Integrative analysis of transcriptome, DNA methylome, and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy.Protein & cell · 2024Article
- Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.European journal of human genetics : EJHG · 2024Observational
- SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.Nature communications · 2024Article
- SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.Life science alliance · 2024Article
- Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy.Frontiers in genetics · 2024Review
- Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.Advances in experimental medicine and biology · 2024Article
- Article
- An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies.Cardiovascular drugs and therapy · 2023Review
- Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues.Communications biology · 2023Article
- RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.EMBO molecular medicine · 2023Article
- The Agonist of Adenosine A1 Receptor Induced Desensitization of delta Opioid receptor-mediated Raf-1/MEK/ERK Signaling by Feedback Phosphorylation of Raf-1-Ser289/296/301.Neurochemical research · 2023Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
backgroundMore than 90% of individuals with Noonan syndrome (NS) with mutations clustered in the CR2 domain of RAF1 present with severe and often lethal hypertrophic cardiomyopathy (HCM). The signaling pathways by which NS RAF1 mutations promote HCM remain elusive, and so far, there is no known treatment for NS-associated HCM.
methodsWe used patient-derived RAF1
resultsWe show that mutant iPSC-derived 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 RAF1 mutant iPSC-derived 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 RAF1 mutant iPSC-derived cardiomyocytes and identifies subsets of genes dysregulated by aberrant MEK1/2 or ERK5 pathways that could contribute to the NS-associated HCM.
conclusionsTaken together, the results of our study identify the molecular mechanisms by which NS RAF1 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.
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