Recipient organisationCardiff UniversitySource-published name: Cardiff University
Funding£1.4M
PeriodNov 2019 — Oct 2025
In plain English
AI plain-English summary
Around 1% of the UK population—over 695,000 people—may be autistic, and roughly 25% of intellectual disability cases have a genetic cause, yet no medications exist to treat the core symptoms of these conditions. This project targets a specific genetic culprit: a chromosomal rearrangement at a region called 16p11.2, which can be either a deletion or a duplication of 27 genes. Patients with the deletion tend to gain weight and have larger heads; those with the duplication lose weight, have smaller heads, and may also develop psychotic symptoms. The researchers have strong evidence that one gene in this region, MAPK3, drives these effects. They will monitor MAPK3 activity in patients’ blood to see if it can serve as a diagnostic marker, and they will build human cellular models—including mini-brain preparations—to test whether experimental drugs can correct MAPK3 levels. If MAPK3 proves to be a valid therapeutic target, this work could open the door to the first treatments that reverse the neurological and metabolic consequences of 16p11.2 rearrangements, rather than just managing symptoms. For now, the research is fundamental: it aims to establish whether a single gene can explain the broad differences between deletion and duplication patients, and whether that gene is druggable.
View original technical description
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.
Jeremy Hall (Co-Investigator)Jonathan Green (Co-Investigator)Marianne Van Den Bree (Co-Investigator)Meng Li (Co-Investigator)Nicholas Bray (Co-Investigator)Riccardo Brambilla (Principal Investigator)
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