Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

Elife. 2022 May 10:11:e72290. doi: 10.7554/eLife.72290.


Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here, we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders.

Keywords: Pitt-Hopkins syndrome; gene therapy; genetics; genomics; mouse; neurodevelopmental disorder; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Facies
  • Hyperventilation
  • Intellectual Disability* / genetics
  • Intellectual Disability* / metabolism
  • Mice
  • Phenotype
  • Transcription Factor 4 / genetics
  • Transcription Factor 4 / metabolism*


  • Tcf4 protein, mouse
  • Transcription Factor 4

Supplementary concepts

  • Pitt-Hopkins syndrome

Associated data

  • GEO/GSE123335
  • GEO/GSE60361