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

Alexis Cooper,Susanne Strand,Florian Lesage,Junaid Akhtar,Ulrich Zechner,Somanath Jagannath,Tamer Butto,Desiree Lucia Fend-Guella,Konstantin Radyushkin,Jochen Roeper,Susann Schweiger,Jennifer Winter,Niklas Hammer

doi:10.1038/s41467-019-13918-4

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.

Highlights

Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause BirkBarel intellectual disability syndrome (BBIDS)
Given the described intellectual disability in BBIDS patients, we examined whether working memory was affected in Kcnk9KO mice
The average percentage of spontaneous alternation made by Kcnk9KOhom, Kcnk9KOmat, and wild type (WT) mice across a 10-min trial was analyzed and revealed a significant reduction of spontaneous alternation by about 10% in both Kcnk9KOhom and Kcnk9KOmat mice compared with WT littermates (Fig. 1b)

Summary

Introduction

Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause BirkBarel intellectual disability syndrome (BBIDS). We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk[9] allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. These findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder. The disease is inherited autosomal dominantly with maternal-only transmission[1], as the KCNK9 gene is embryonically paternally silenced (imprinted) in man and mouse. We demonstrate partial behavioral rescue in these animals compared with full knockout animals and show that epigenetic manipulation stimulates Kcnk9pat expression sufficiently, to rescue the behavioral phenotypes, thereby opening new avenues for treatment of cognitive dysfunctions in BBIDS

Methods

Results

Conclusion