Grant: Project Grant

Truncating mutations in the X-linked gene PTCHD1 have been shown to cause autism spectrum disorder (ASD) and/or intellectual disability (ID). While the link between gene and disease is very strong, our understanding of what PTCHD1 does is very weak. Initial suggestions for a role in the Hedgehog/Smoothened signalling pathway now look likely to be incorrect. The project outlined here aims to explore the function of PTCHD1, its role in neurodevelopmental disorders such as ASD and ID, and its relationship to ASD/ID gene networks. This will be done through three main aims: 1. studying the function of the protein, what molecules does it interact with and how; 2. how disruption of PTCHD1 leads to neurodevelopmental disorders, using studies of knockout mice and zebrafish; 3. refining the phenotype- what clinical features are shared by patients with disrupted PTCHD1, and how does this relate to the protein's function, and the phenotypes observed in the mice and zebrafish. For our zebrafish studies, we also aim to look for larval phenotypes that may then be used for high-throughput screening for therapeutic molecules. We have assembled a multi-disciplinary team with expertise across four diverse areas- namely protein function, animal neurobehaviour, molecular genetics, and clinical genetics- who have the background, experience, and motivation, to perform the proposed work, as well as promising preliminary data, that together will lead to high-impact discoveries.