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

Nat Commun. 2020 Jan 24;11(1):480. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Craniofacial Abnormalities / drug therapy
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / metabolism*
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Genomic Imprinting
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / metabolism*
  • Humans
  • Intellectual Disability / drug therapy
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism*
  • Locus Coeruleus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Hypotonia / drug therapy
  • Muscle Hypotonia / genetics*
  • Muscle Hypotonia / metabolism*
  • Mutation
  • Phenotype
  • Phenylenediamines / pharmacology
  • Potassium Channels / deficiency
  • Potassium Channels / genetics*
  • Potassium Channels / metabolism
  • Up-Regulation / drug effects

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Phenylenediamines
  • Potassium Channels
  • TASK3 protein, mouse
  • tacedinaline

Supplementary concepts

  • Birk-Barel Mental Retardation Dysmorphism Syndrome