PMID- 31980599 OWN - NLM STAT- MEDLINE DCOM- 20200413 LR - 20210123 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 11 IP - 1 DP - 2020 Jan 24 TI - Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome. PG - 480 LID - 10.1038/s41467-019-13918-4 [doi] LID - 480 AB - Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9(pat)) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder. FAU - Cooper, Alexis AU - Cooper A AD - Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. FAU - Butto, Tamer AU - Butto T AD - Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Staudingerweg 9, 55128, Mainz, Germany. FAU - Hammer, Niklas AU - Hammer N AD - Institute of Neurophysiology, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. FAU - Jagannath, Somanath AU - Jagannath S AD - Institute of Neurophysiology, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. FAU - Fend-Guella, Desiree Lucia AU - Fend-Guella DL AD - Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. FAU - Akhtar, Junaid AU - Akhtar J AD - Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Staudingerweg 9, 55128, Mainz, Germany. FAU - Radyushkin, Konstantin AU - Radyushkin K AD - Focus Program Translational Neuroscience, Center for Rare Diseases, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. FAU - Lesage, Florian AU - Lesage F AUID- ORCID: 0000-0002-4406-7106 AD - Universite Cote d'Azur, INSERM, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moleculaire et Cellulaire, Labex ICST, 660, route des Lucioles Sophia Antipolis, 06560, Valbonne, France. FAU - Winter, Jennifer AU - Winter J AD - Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. AD - Focus Program Translational Neuroscience, Center for Rare Diseases, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. FAU - Strand, Susanne AU - Strand S AD - Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Strasse 63, 55131, Mainz, Germany. FAU - Roeper, Jochen AU - Roeper J AD - Institute of Neurophysiology, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. FAU - Zechner, Ulrich AU - Zechner U AD - Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. u.zechner@senckenberg-humangenetik.de. AD - Senckenberg Center of Human Genetics, Weismullerstrasse 50, 60314, Frankfurt, Germany. u.zechner@senckenberg-humangenetik.de. FAU - Schweiger, Susann AU - Schweiger S AD - Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de. AD - Focus Program Translational Neuroscience, Center for Rare Diseases, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de. AD - Center for Orphan Diseases of the Central Nervous System, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de. AD - German Resilience Centre, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200124 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Benzamides) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Histones) RN - 0 (Phenylenediamines) RN - 0 (Potassium Channels) RN - 0 (TASK3 protein, mouse) RN - UMF554N5FG (tacedinaline) RN - Birk-Barel Mental Retardation Dysmorphism Syndrome SB - IM MH - Animals MH - Behavior, Animal MH - Benzamides MH - Brain/metabolism MH - Craniofacial Abnormalities/drug therapy/*genetics/*metabolism MH - Disease Models, Animal MH - Female MH - Gene Knockdown Techniques MH - Genomic Imprinting MH - Histone Deacetylase Inhibitors/pharmacology MH - Histones/*metabolism MH - Humans MH - Intellectual Disability/drug therapy/*genetics/*metabolism MH - Locus Coeruleus/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle Hypotonia/drug therapy/*genetics/*metabolism MH - Mutation MH - Phenotype MH - Phenylenediamines/pharmacology MH - Potassium Channels/deficiency/*genetics/metabolism MH - Up-Regulation/drug effects PMC - PMC6981138 COIS- The authors declare no competing interests. EDAT- 2020/01/26 06:00 MHDA- 2020/04/14 06:00 PMCR- 2020/01/24 CRDT- 2020/01/26 06:00 PHST- 2018/12/18 00:00 [received] PHST- 2019/12/05 00:00 [accepted] PHST- 2020/01/26 06:00 [entrez] PHST- 2020/01/26 06:00 [pubmed] PHST- 2020/04/14 06:00 [medline] PHST- 2020/01/24 00:00 [pmc-release] AID - 10.1038/s41467-019-13918-4 [pii] AID - 13918 [pii] AID - 10.1038/s41467-019-13918-4 [doi] PST - epublish SO - Nat Commun. 2020 Jan 24;11(1):480. doi: 10.1038/s41467-019-13918-4.