Grant: Project Grant

Truncating mutations in the X-linked gene PTCHD1 have been shown to cause autism spectrum disorder and/or intellectual disability. While the link between gene and disease is very strong, our understanding of what PTCHD1 does in the brain is still weak. For patients identified with DNA mutations in PTCHD1 that prevent it from making its protein, the integrated healthcare package for the families, including diagnostics, counselling and family planning, is clear. However, in the majority of cases, the DNA mutation changes one unit of the protein to another, and, as the effect this would have on the protein made by the gene is unclear, the healthcare package for the family changes, and many services would not be accessible. The project outlined here aims to explore the function of PTCHD1 and its role in neurodevelopmental disorders such as autism and intellectual disability. This will be done through four main aims: 1. Using studies of knockout mice: how does disruption of PTCHD1 lead to neurodevelopmental disorders? What mouse phenotypes overlap with clinical features in patients with disrupted PTCHD1? How does this relate to the protein's function and isoforms? 2. Understanding short PTCHD1 (isoform c) and social deficits by AAV-gene replacement in exon3 PTCHD1 mice, or knockdown in the exon2 PTCHD1 mice. 3. Studying the function of the protein: with what molecules does it interact? 4. Diagnostics: develop assays that can be used to determine whether PTCHD1 variants are contributing to the disease. We have assembled a multi-disciplinary team with expertise across four diverse areas- namely protein function, animal neurobehaviour, molecular genetics, and clinical diagnostics- 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.