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Nat Commun. 2020 Jan 24;11(1):480. doi: 10.1038/s41467-019-13918-4.

Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome.

Author information

1
Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
2
Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Staudingerweg 9, 55128, Mainz, Germany.
3
Institute of Neurophysiology, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
4
Focus Program Translational Neuroscience, Center for Rare Diseases, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
5
Université Côte d'Azur, INSERM, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, 660, route des Lucioles Sophia Antipolis, 06560, Valbonne, France.
6
Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 63, 55131, Mainz, Germany.
7
Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. u.zechner@senckenberg-humangenetik.de.
8
Senckenberg Center of Human Genetics, Weismüllerstraße 50, 60314, Frankfurt, Germany. u.zechner@senckenberg-humangenetik.de.
9
Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de.
10
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.
11
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.
12
German Resilience Centre, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susann.schweiger@unimedizin-mainz.de.

Abstract

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 (Kcnk9pat) 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.

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