Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder, predominantly caused by a deletion on the long arm of chromosome 15. This deletion eliminates a group of genes called HBII-85 whose function is currently unknown. Therefore, this proposal aims to investigate the underlaying molecular mechanisms behind the loss of HBII-85 and how this loss translates into the disease of PWS. Preliminary sequencing studies in our lab suggest that seven of the HBII-85 genes are processed as microRNAs (miRNAs) and we aim to verify that these can indeed function as miRNAs. MiRNAs control gene function by binding to a portion of the gene sqeunce, effectively reducing gene activity. These regulatory molecules have also been shown to be involved in a number of neurodevelopmental and psychiatric disorders. We propose that loss of these miRNAs originating form HBII-85 could be a main cause of PWS and want to characterize the widespread effects of this loss in two cell based models. The first model characterizes the function of thse molecules by demonstrating their ability to change gene expression. In the second model we will use cells from a PWS patient and apply a novel technique called immunoprecipitation. This technique uses an antibody to capture a specific protein, called Ago2, which contains the miRNAs of interest and facilitates the processing of their respective target genes. Thus, using these two models, we will be in a position to identify other unknown genetic mechanisms underlying the cause of PWS.
Currently, no effective treatment for patients with PWS, aside from basic symptom management, is available. By studying miRNAs originating from the HBII-85 genes, the proposed study shifts the current paradigm of PWS research. The results from our study could establish a completely novel venue for therapy, which has the potential to benefit patients with PWS and their families tremendously.