Development of an in vitro disease model system for dissecting the epigenetic mechanisms underlying pathogenesis of Kabuki syndrome

Kabuki syndrome is a rare genetic disorder characterized by a wide and variable spectrum of congenital abnormalities. Among the most common clinical abnormalities patients may experience a characteristic facial appearance , postnatal growth deficiency , visceral and skeletal abnormalities , mental retardation, moderate and immunological dysfunction . Mutations of the genes MLL2 and KDM6A have been identified as the main cause of the onset of Kabuki Syndrome . Both genes code for proteins that are part of the chromatin regulatory complex named MLL4 . The main objective of this project is to investigate the pathological role of the mutated MLL4 complex in the etiology of the Kabuki Syndrome (KS). The lack of cellular and animal models has limited the study of the molecular mechanisms underlying the Kabuki Syndrome. To overcome these limitations, we will develop an experimental model that will allow us to assess the effects of these mutations on cellular events that modulated by MLL2 and KDM6A in mesenchymal stem cells. This experimental approach will allow to better understand the molecular mechanism underlying the Kabuki Syndrome and thus promote the development of new therapeutic strategies for patients with this disease.