title: Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.
abstract: Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/βGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. hbjorns1@jhmi.edu.
authors.forename: Hans T
authors.initials: HT
authors.lastname: Bjornsson
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Benjamin
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Kennedy Krieger Institute, Baltimore, MD 21205, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Weissman
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gerber
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Kennedy Krieger Institute, Baltimore, MD 21205, USA.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Vaurio
authors.affiliation: Brain Science Institute, Neurology Department, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Potter
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Biostatistics, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Kasper D
authors.initials: KD
authors.lastname: Hansen
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005145:Face / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D006402:Hematologic Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D055495:Neurogenesis; D015837:Vestibular Diseases / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; C120898:KMT2D protein, human; D009363:Neoplasm Proteins