Neurodevelopmental alterations in Weaver syndrome: a cell reprogramming-based approach to the elucidation of epigenetic disease mechanisms

Weaver syndrome is a rare and so far neglected disease characterized by overgrowth and intellectual disability associated with craniofacial dismorphism. Weaver syndrome has been recently associated with the genetic defect in a protein, called EZH2, that chemically modifies one of the proteins around which DNA is wrapped within our cells. This protein is called Histone H3, and its modification by EZH2 is important in controlling how genes are expressed during development. However, while much is known about the function of EZH2 in orchestrating development, there is no understanding of how the genetic defect found in Weaver syndrome patients brings about the cardinal manifestations associated to the disease. In particular the role of EZH2 in the function of mature neurons, ie. once the cerebral cortex has completed its development, remains unclear. The aim of our project is to define how the genetic defect of Weaver syndrome causes malfunction or abnormal development of cortical neurons, in order to shed light on the mechanisms responsible for cognitive impairment in Weaver syndrome patients. To this end we use a very innovative technological approach to fill the gap between what is known on the function of EZH2 and the clinical manifestations of this disease. Specifically, we use fibroblasts from small skin biopsies, provided by Weaver syndrome patients, and we reprogram them into pluripotent stem cells which can then be differentiated, in vitro, into cortical neurons. We will perform on these patient-specific cells a wide range of advanced molecular analyses to define what are the key genes whose function is altered as a result of the genetic defects in EZH2. Furthermore, the characterization of pluripotent stem cells from Weaver patients will become an important tool for the Weaver syndrome research community, since these cells can be used to study the effect of Weaver mutations on the full range of cell types involved in the clinical manifestations of the disease.