Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome

Hum Mutat. 2009 Apr;30(4):669-76. doi: 10.1002/humu.20935.


Pitt-Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E-protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue-specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Abnormalities, Multiple / physiopathology
  • Adolescent
  • Adult
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Dimerization
  • Electroencephalography
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Developmental
  • HeLa Cells
  • Humans
  • Hyperventilation / pathology
  • Immunohistochemistry
  • In Situ Hybridization
  • Infant
  • Intellectual Disability / pathology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Syndrome
  • Transcription Factor 4
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Young Adult


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Luciferases