ArticleThe Journal of clinical investigation2015
RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 86 citations in OpenAlex.
- Dominant-negative effects of Weaver syndrome-associated EZH2 variants.Genes & development · 2025Article
- RNA-seq analysis of wild-type and mutated TBPL1 gene in breast cancer cells lines through CRISPR/Cas9 approach reveals novel molecular signatures.Scientific reports · 2025Article
- Molecular Regulation of Palatogenesis and Clefting: An Integrative Analysis of Genetic, Epigenetic Networks, and Environmental Interactions.International journal of molecular sciences · 2025Review
- MLL4 regulates postnatal palate growth and midpalatal suture development.Frontiers in cell and developmental biology · 2025Article
- Role of histone-lysine N-methyltransferase 2D (KMT2D) in MEK-ERK signaling-mediated epigenetic regulation: a phosphoproteomics perspective.Frontiers in bioinformatics · 2025Article
- MLL4 regulates postnatal palate growth and midpalatal suture development.bioRxiv : the preprint server for biology · 2024Article
- Genetic and Phenotypic Spectrum ofDiagnostics (Basel, Switzerland) · 2024Article
- Establishment of a novel cellular model for Alzheimer's disease in vitro studies.Experimental neurology · 2024Article
- An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants.JCI insight · 2024Article
- RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.Journal of clinical and translational hepatology · 2024Article
- Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet).Journal of clinical immunology · 2024Observational
- Illuminating the Genetic Basis of Congenital Heart Disease in Patients with Kabuki Syndrome.Diagnostics (Basel, Switzerland) · 2024Article
- Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates.NPJ genomic medicine · 2024Article
- Knockdown of Kmt2d leads to growth impairment by activating the Akt/β-catenin signaling pathway.G3 (Bethesda, Md.) · 2024Article
- 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
- Pulmonary hypertension- a novel phenotypic hypothesis of Kabuki syndrome: a case report and literature review.BMC pediatrics · 2023Review
- Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes.Familial cancer · 2023Review
- Third reported patient with RAP1B-related syndromic thrombocytopenia and novel clinical findings.American journal of medical genetics. Part A · 2022Article
- Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
28 authors at 15 institutions in 10 countries.
Funding
Abstract
The genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.
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