ArticleThe Journal of clinical investigation2011
MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) 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 140 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
140 citing papers in PubMed, 1 synthesis or guideline pooled it, 230 citations in OpenAlex.
- Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.Frontiers in pediatrics · 2025Pooled it
- 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
- Clinical consensus guidelines for the management of Noonan syndrome in Japan.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2026Article
- A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.Nature communications · 2026Article
- Trametinib Therapy for Hypertrophic Cardiomyopathy and Pulmonary Hypertension in a Child With RAF1-Related Noonan Syndrome (p.Ser257Leu): A Case Report.Clinical case reports · 2026Article
- Tailored therapeutics for cardiomyopathies.Nature reviews. Cardiology · 2025Review
- Mechano-energetic uncoupling in heart failure.Nature reviews. Cardiology · 2025Review
- Research progress on programmed cell death of cardiomyocytes in pressure-overload hypertrophic cardiomyopathy.Apoptosis : an international journal on programmed cell death · 2025Review
- 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
- Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy.JACC. Basic to translational science · 2025Article
- Promising But Not Yet the Promised Land.JACC. Basic to translational science · 2025Article
- ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.BMC medical genomics · 2024Article
- Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice.JCI insight · 2024Article
- Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy.Journal of the American College of Cardiology · 2024Article
- Review
- Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.Life (Basel, Switzerland) · 2024Review
- Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning.Disease models & mechanisms · 2024Article
- Review
80 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%-5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1(L613V) mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies.
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Registered trials
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.