Molecular mechanisms of transcription factor 4 in Pitt-Hopkins syndrome

MD Rannals, BJ Maher - Current genetic medicine reports, 2017 - Springer
Current genetic medicine reports, 2017Springer
Abstract 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 …
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.
Summary
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.
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