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

Alexis Cooper, Tamer Butto, Niklas Hammer, Somanath Jagannath, Desiree Lucia Fend-Guella, Junaid Akhtar, Konstantin Radyushkin, Florian Lesage, Jennifer Winter, Susanne Strand, Jochen Roeper, Ulrich Zechner () and Susann Schweiger ()
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Alexis Cooper: University Medical Center of the Johannes Gutenberg University Mainz
Tamer Butto: Johannes Gutenberg University Mainz
Niklas Hammer: Goethe University Frankfurt
Somanath Jagannath: Goethe University Frankfurt
Desiree Lucia Fend-Guella: University Medical Center of the Johannes Gutenberg University Mainz
Junaid Akhtar: Johannes Gutenberg University Mainz
Konstantin Radyushkin: University Medical Center of the Johannes Gutenberg University Mainz
Florian Lesage: Université Côte d’Azur, INSERM, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST
Jennifer Winter: University Medical Center of the Johannes Gutenberg University Mainz
Susanne Strand: University Medical Center of the Johannes Gutenberg University Mainz
Jochen Roeper: Goethe University Frankfurt
Ulrich Zechner: University Medical Center of the Johannes Gutenberg University Mainz
Susann Schweiger: University Medical Center of the Johannes Gutenberg University Mainz

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13918-4

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