Modelling Pitt-Hopkins syndrome in Drosophila

Genetic changes called variants in the gene called TCF4 lead to a severe neurodevelopmental syndrome characterized by movement abnormalities, intellectual disability, autism, seizures, and distinct facial features. The disorder has been named Pitt-Hopkins syndrome (PTHS). The TCF4 protein is involved in regulating other genes and is involved in a wide variety of processes that help cells grow and develop into specific cell types. It is hard to study TCF4 in most animal models as complete loss of this gene leads to early loss of the embryo. However, fruit flies offer an alternative.  In the fly we can selectively remove the TCF4 gene, called daughterless, only in adult fly neurons or adult fly glia (nervous system support cells). This way we can assess the role of TCF4 in the adult fly brain and find features in flies that we can study with select variant drugs. Indeed, some anti-inflammatory drugs may increase TCF4 levels and may be effective in our proposed fly model. Finally, by collaborating with the Canadian Prairie Metabolic Network we have identified a patient with developmental delay with a novel, never before seen variant in the TCF4 gene. We propose to study this novel variant as well as variants previously identified in other patients to try to understand why there is a wide range in symptoms for individuals with PTHS.