ArticleScientific reports2018
Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 39 citations in OpenAlex.
- Advancing edge-based clustering and graph embedding for biological network analysis: a case study in RASopathies.Briefings in bioinformatics · 2025Article
- Applications of Gene Editing and Nanotechnology in Stem Cell-Based Therapies for Human Diseases.Stem cell reviews and reports · 2025Review
- Differences between lung adenocarcinoma and lung squamous cell carcinoma: Driver genes, therapeutic targets, and clinical efficacy.Genes & diseases · 2025Review
- Molecular Regulation of Palatogenesis and Clefting: An Integrative Analysis of Genetic, Epigenetic Networks, and Environmental Interactions.International journal of molecular sciences · 2025Review
- O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome.The Journal of biological chemistry · 2024Review
- KMT2D regulates activation, localization, and integrin expression by T-cells.Frontiers in immunology · 2024Article
- SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder.Birth defects research · 2023Review
- Epigenetic disorders: Lessons from the animals-animal models in chromatinopathies.Frontiers in cell and developmental biology · 2022Review
- Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome.Molecular therapy. Methods & clinical development · 2021Article
- Role of epigenetics and miRNAs in orofacial clefts.Birth defects research · 2020Review
- Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation.Italian journal of pediatrics · 2020Article
- Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.Human molecular genetics · 2020Article
- The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration.Human molecular genetics · 2020Article
- A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma.Frontiers in oncology · 2020Article
- Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome.PLoS biology · 2019Article
- COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer.Cancer letters · 2019Review
- Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.American journal of human genetics · 2019Article
- Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis.Frontiers in bioengineering and biotechnology · 2019Article
- Analysis of Single Nucleotide Variants in CRISPR-Cas9 Edited Zebrafish Exomes Shows No Evidence of Off-Target Inflation.Frontiers in genetics · 2019Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function of RAP1A, a RAF1 regulator, can activate the RAS/MAPK pathway and cause KS, an observation recapitulated in other genetic models of the disorder. These data suggested that suppression of this signaling cascade might be of therapeutic benefit for some features of KS. To pursue this possibility, we performed a focused small molecule screen of a series of RAS/MAPK pathway inhibitors, where we tested their ability to rescue disease-relevant phenotypes in a zebrafish model of the most common KS locus, kmt2d. Consistent with a pathway-driven screening paradigm, two of 27 compounds showed reproducible rescue of early developmental pathologies. Further analyses showed that one compound, desmethyl-Dabrafenib (dmDf), induced no overt pathologies in zebrafish embryos but could rescue MEK hyperactivation in vivo and, concomitantly, structural KS-relevant phenotypes in all KS zebrafish models (kmt2d, kmd6a and rap1). Mass spectrometry quantitation suggested that a 100 nM dose resulted in sub-nanomolar exposure of this inhibitor and was sufficient to rescue both mandibular and neurodevelopmental defects. Crucially, germline kmt2d mutants recapitulated the gastrulation movement defects, micrognathia and neurogenesis phenotypes of transient models; treatment with dmDf ameliorated all of them significantly. Taken together, our data reinforce a causal link between MEK hyperactivation and KS and suggest that chemical suppression of BRAF might be of potential clinical utility for some features of this disorder.
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