Pilot Study to Establish the Relevance of the T-dark Gene HIRIP3 in 16p11.2 CNV Syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

One of the most common genetic causes of conditions such as autism, epilepsy and intellectual disability is a small chromosomal deletion called 16p11.2. This region contains several genes, but for many of them, we still do not understand what they do or how they might contribute to the symptoms. One of these genes is HIRIP3, which is extremely understudied and belongs to a group of so-called “Tdark” genes—genes that scientists know exist, but for which almost no functional information is available. This project focuses on understanding what happens when HIRIP3 is reduced in the brain, as occurs in individuals with a 16p11.2 deletion. Although its role in the brain is unknown, HIRIP3 is known to bind to another protein called HIRA, which helps regulate how DNA is organized inside cells. We believe that HIRIP3 may help fine-tune gene activity in neurons by working together with HIRA. If this balance is disrupted, it could interfere with brain development and function. To test this idea, we will use gene-silencing tools to reduce the levels of HIRIP3 in a specific brain region called the hippocampus, which is important for memory, emotions and social behavior. We will then analyze how gene expression changes in the brain and how this affects behaviors that are often altered in children with 16p11.2 deletions. By studying this almost completely uncharacterized gene in a disease-relevant context, this project aims to shed light on a possible molecular mechanism behind neurodevelopmental disorders and open the door to future therapies.