Current Genetic Medicine Reports

, Volume 5, Issue 1, pp 1–7 | Cite as

Molecular Mechanisms of Transcription Factor 4 in Pitt-Hopkins Syndrome

  • Matthew D. RannalsEmail author
  • Brady J. Maher
Neurogenetics and Psychiatric Genetics (M Hiltunen and DR Marenda, Section Editors)
Part of the following topical collections:
  1. Neurogenetics and Psychiatric Genetics


Purpose of Review

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from mutations of the clinically pleiotropic transcription factor 4 (TCF4) gene. Mutations in the genomic locus of TCF4 on chromosome 18 have been linked to multiple disorders including 18q syndrome, schizophrenia, Fuch’s corneal dystrophy, and sclerosing cholangitis. For PTHS, TCF4 mutation or deletion leads to the production of a dominant negative TCF4 protein and/or haploinsufficiency that result in abnormal brain development. The biology of TCF4 has been studied for several years in regard to its role in immune cell differentiation, although its role in neurodevelopment and the mechanisms resulting in the severe symptoms of PTHS are not well studied.

Recent Findings

Here, we summarize the current understanding of PTHS and recent findings that have begun to describe the biological implications of TCF4 deficiency during brain development and into adulthood. In particular, we focus on recent work that has looked at the role of TCF4 biology within the context of PTHS and highlight the potential for identification of therapeutic targets for PTHS.


PTHS research continues to uncover mutations in TCF4 that underlie the genetic cause of this rare disease, and emerging evidence for molecular mechanisms that TCF4 regulates in brain development and neuronal function is contributing to a more complete picture of how pathology arises from this genetic basis, with important implications for the potential of future clinical care.


Pitt-Hopkins syndrome Transcription factor 4 TCF4 ITF2 SEF2 E2-2 Autism spectrum 



This work was supported by NIH grant (R56MH104593) and Pitt-Hopkins Research Foundation Award to B.J.M.

Compliance with Ethics Standards

Conflict of Interest

Matthew D. Rannals declares that he has no conflict of interest.

Brady J. Maher reports grants from the NIH/NIMH during the conduct of study. He reports employment at the Lieber Institute for Brain Development and grants from NIMH outside of the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as : • Of importance

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Copyright information

© Springer Science + Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Neurobiology, School of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Lieber Institute for Brain DevelopmentJohns Hopkins Medical CampusBaltimoreUSA
  3. 3.Department of Psychiatry and Behavioral SciencesJohns Hopkins School of MedicineBaltimoreUSA
  4. 4.Department of NeuroscienceJohns Hopkins School of MedicineBaltimoreUSA

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