Genetic and epigenetic mechanisms associated with Phelan-McDermid syndrome clinical variability

Abstract

Phelan-McDermid Syndrome (PMS) is a rare genetic disease characterized by global developmental delay, Intellectual Disability (ID) and Autism Spectrum Disorder (ASD), associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been described as a major cause of neurological symptoms of PMS, it cannot explain the spectrum of clinical variability. SHANK3 modulates several molecular pathways, being Wnt/beta-catenin pathway is one of them. Under normal conditions, beta-catenin interacts with SHANK3 in the synaptic regions, and modulates the actin cytoskeleton. However, with decreased SHANK3 levels, beta-catenin are translocated to the nucleus, and can activate transcription of epigenetic control genes such as HDAC2. How the clinical variability can change with the different levels of beta-catenin, and what the effects of activation of transcription factors by beta-catenin, are issues that have not yet been elucidated. Thus, this project aims to investigate the genetic and epigenetic mechanisms of PMS caused by beta-catenin/SHANK3 relationship, and identify factors that regulate the clinical variability associated with SHANK3 deficiency. For this, we will use neural cells derived from iPSCs of PMS patients and healthy controls, which allow us to recapitulate early stages of neuronal development. The profile of chromatin accessibility and gene expression among PMS samples will be analyzed in order to investigate the effect of overexpression of epigenetic modifiers. With this project we hope to contribute to a better understanding of mechanisms responsible for clinical variability in PMS, and provide subsidies for the development of future treatments as well as development of markers to predict prognosis. (AU)