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; Susann Schweiger

doi:10.1038/s41467-019-13918-4

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, Susann Schweiger

Developmental Neurobiology

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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 (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.

Original language	English
Article number	480
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13918-4
Publication status	Published - 1 Dec 2020

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Cooper, A., Butto, T., Hammer, N., Jagannath, S., Fend-guella, D. L., Akhtar, J., Radyushkin, K., Lesage, F., Winter, J., Strand, S., Roeper, J., Zechner, U., & Schweiger, S. (2020). Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome. Nature Communications, 11(1), Article 480. https://doi.org/10.1038/s41467-019-13918-4

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title = "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 (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. ",

author = "Alexis Cooper and Tamer Butto and Niklas Hammer and Somanath Jagannath and Fend-guella, {Desiree Lucia} and Junaid Akhtar and Konstantin Radyushkin and Florian Lesage and Jennifer Winter and Susanne Strand and Jochen Roeper and Ulrich Zechner and Susann Schweiger",

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Cooper, A, Butto, T, Hammer, N, Jagannath, S, Fend-guella, DL, Akhtar, J, Radyushkin, K, Lesage, F, Winter, J, Strand, S, Roeper, J, Zechner, U & Schweiger, S 2020, 'Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome', Nature Communications, vol. 11, no. 1, 480. https://doi.org/10.1038/s41467-019-13918-4

TY - JOUR

T1 - Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome

AU - Cooper, Alexis

AU - Butto, Tamer

AU - Hammer, Niklas

AU - Jagannath, Somanath

AU - Fend-guella, Desiree Lucia

AU - Akhtar, Junaid

AU - Radyushkin, Konstantin

AU - Lesage, Florian

AU - Winter, Jennifer

AU - Strand, Susanne

AU - Roeper, Jochen

AU - Zechner, Ulrich

AU - Schweiger, Susann

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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.

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DO - 10.1038/s41467-019-13918-4

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 480

ER -

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

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