Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2

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Human genetics has enabled us to identify specific gene variations which are associated with neurodevelopment disorders (NDD) such intellectual disability (ID) and Autism spectrum disorder (ASD). Just over 1% of the UK population are believed to be on the autism spectrum, meaning over 695,000 people in the UK may be autistic. Intellectual disability affects about 2-3% of the general population, with at least 25% of cases likely to be caused by a genetic predisposition.There is currently no cure for ASD/ID and no medications to treat the main symptoms of these disorders. This project aims to improve the chances of developing medicines able to reverse the effects of these genetic alterations. Among the most common genetic forms of ASD/ID lie chromosomal modifications, which cause either a deletion or a duplication of a group of genes. Interestingly, there are important differences between the duplication and the deletion patients such as metabolic changes (tendency to increase weight in the deletion and decrease weight in the duplication) and craniofacial abnormalities (deletion is associated with increased head size whereas the duplication is associated with decreased size). Importantly, duplication patients may be more susceptible to psychotic symptoms in addition to ID/ASD.In the 16p11.2 chromosomal region there are 27 distinct genes but we currently do not know their contribution to the pathological state. We have gathered strong preliminary evidence that one of these genes, MAPK3, may play a prominent role in the development of these ASD/ID forms associated to the 16p11.2 region. In this project, we will investigate the role of MAPK3 in both duplication and deletion patients by monitoring in the blood its activity. The goal is to be able to use MAPK3 as a tool to help both diagnosis and future treatments.We will also generate sophisticated human cellular models and mini-brain preparations to study how MAPK3 levels can be corrected and possibly restored using novel experimental drugs.At the end of the project we will have demonstrate whether MAPK3 is a valid therapeutic target for the diagnosis and the treatment of 16p11.2 duplication and deletion patients.