title: A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome.
abstract: Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeomice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeomice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
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.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Genay O
authors.initials: GO
authors.lastname: Pilarowski
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Giovanni A
authors.initials: GA
authors.lastname: Carosso
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Loyal A
authors.initials: LA
authors.lastname: Goff
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Pediatrics at the Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Vernon
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
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; hbjorns1@jhmi.edu.|Department of Pediatrics at the Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik 101, Iceland.
authors.forename: Hans T
authors.initials: HT
authors.lastname: Bjornsson
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000015:Abnormalities, Multiple / Q000178:diet therapy* / Q000235:genetics; D000818:Animals; D055423:Diet, Ketogenic / Q000379:methods*; D004195:Disease Models, Animal; D005145:Face / Q000002:abnormalities*; D006402:Hematologic Diseases / Q000178:diet therapy* / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D056466:Histone Demethylases / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000096:biosynthesis*; D008607:Intellectual Disability / Q000178:diet therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D015837:Vestibular Diseases / Q000178:diet therapy* / Q000235:genetics
chemical_list: D006657:Histones; D051788:Myeloid-Lymphoid Leukemia Protein; D056466:Histone Demethylases; C111778:Utx protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse; D020155:3-Hydroxybutyric Acid
keywords: adult neurogenesis; epigenetics; histone machinery; intellectual disability; ketone bodies