Role of Kctd20 gene in the pathogenesis of Phelan McDermid syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

Phelan McDermid Syndrome (PMS) is a rare and incurable disease, generally underrated by public funding and big pharmaceutical companies. PMS is characterized by intellectual disability, autistic features and neuropsychiatric symptoms. More than 1500 cases have been reported worldwide. PMS is now considered to be a relatively common cause of autism and intellectual disability, accounting for between 0.5% and 2.0% of cases. The lack of effective therapies for PMS stresses the urgency with which pathogenic mechanisms underlying the disorder need to be identified. Through, RNAseq analysis we found a significant reduction in Kctd20 expression in cortex and striatum of Shank3 mouse model of PMS. Kctd20 is a poorly studied gene that seems to have a role in activating AKT signaling. Our hypothesis is that deregulated expression of Kctd20 due to Shank3 absence causes excess Akt inactivation leading to behavioral and functional alteration found in Shank3 KO mice. In this project we aim to characterize Kctd20, a gene whose function is still unknown especially in neurons. The proposed study will establish the relationship between the functional and cognitive defects associated to SHANK3-related syndromes and Kctd20 expression and molecular function paving the way for possible therapeutic insights for PMS. Moreover, defining Kctd20 molecular activities will be important not only for patients affected by PMS or SHANK3 deletion but will reveal also more on the network of genes required for the correct development of the nervous system and ultimately will be of help also for research on autism spectrum disorders.