Molecular Mechanisms of Transcription Factor 4 in Pitt-Hopkins Syndrome

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.