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

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.

SUBMITTER: Cooper A

PROVIDER: S-EPMC6981138 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Cooper Alexis A Butto Tamer T Hammer Niklas N Jagannath Somanath S Fend-Guella Desiree Lucia DL Akhtar Junaid J Radyushkin Konstantin K Lesage Florian F Winter Jennifer J Strand Susanne S Roeper Jochen J Zechner Ulrich U Schweiger Susann S

Nature communications 20200124 1

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<sup>pat</sup>) 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 fu ...[more]

PMID: 31980599

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