Una strategia integrata per comprendere i meccanismi genetici ed epigenetici alla base della sindrome Kabuki

Kabuki Syndrome is a rare genetic disease characterized by distinctive facial appearance, growth retardation, multiple congenital anomalies, skeletal and cardiac abnormalities, immunological defects and varying degrees of mental retardation. Kabuki syndrome is caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes, although it’s not yet known how these mutations may determine the set of clinical signs that characterize the syndrome. The research project aims to define the molecular and cellular processes that, as result of KMT2D and KDM6A mutations, are altered in Kabuki syndrome patients, causing the various clinical manifestations of the disease. The study was conducted on various patients’ cell lines such as neuronal cells and blood lymphocytes, two relevant tissues for the disease’s associated deficiencies such as mental retardation and immunological defects. Using the RNA-Seq technology, altered cellular processes have been identified in patients’ cells, such as the genesis and function of neuronal axons that could have a role in the common intellectual disability syndrome. Moreover, genome regions and genes directly controlled by KMT2D and KDM6A have been identified by ChiPseq technique, genes whose characterization is currently in progress. Mouse model defective of KDM6A gene has been also designed and analysed. The detailed analysis of the animal model is allowing to define the molecular basis that cause the immune defects seen in Kabuki patients, such as the reduced quantity of immunoglobulins. The data obtained, identified the cellular processes and the genes that are deregulated as consequence of KMT2D and KDM6A alterations. The results of this project have the potential to lead to the identification of new therapeutic targets that could be tested in the future as potential therapies.