ArticlePLoS biology2019
Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Metabolomic analysis of children with congenital heart disease complicated by neurological developmental abnormalities and CHD7 mutations.Frontiers in genetics · 2026Article
- Defects inFrontiers in genetics · 2026Article
- Deficiency of KMT2D causes autistic-like behavior in mice and zebrafish.Communications biology · 2025Article
- Distinct roles of COMPASS subunits to Drosophila heart development.Biology open · 2024Article
- Illuminating the Genetic Basis of Congenital Heart Disease in Patients with Kabuki Syndrome.Diagnostics (Basel, Switzerland) · 2024Article
- Epigenetic regulation of craniofacial development and disease.Birth defects research · 2024Review
- Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation ofInternational journal of molecular sciences · 2023Article
- SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder.Birth defects research · 2023Review
- Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1.Birth defects research · 2023Review
- Loss of Histone Methyltransferase KMT2D Attenuates Angiogenesis in the Ischemic Heart by Inhibiting the Transcriptional Activation of VEGF-A.Journal of cardiovascular translational research · 2023Article
- The Roles of Histone Lysine Methyltransferases in Heart Development and Disease.Journal of cardiovascular development and disease · 2023Review
- Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury.Frontiers in cell and developmental biology · 2022Article
- Epigenetic disorders: Lessons from the animals-animal models in chromatinopathies.Frontiers in cell and developmental biology · 2022Review
- Delta-like ligand 4 level in colorectal cancer is associated with tumor aggressiveness and clinical outcome.Cancer biomarkers : section A of Disease markers · 2022Article
- Article
- Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases.The American journal of pathology · 2021Review
- Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research.Journal of developmental biology · 2021Review
- The Zebrafish Cardiac Endothelial Cell-Roles in Development and Regeneration.Journal of cardiovascular development and disease · 2021Review
- Review
- Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
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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.