John Parant, Ph.D., UAB, and Sara Coper, Ph.D., HudsonAlpha to utilize whole genome CRISPR/Cas9 technology to investigate Robert syndrome in depth

Sister chromatid cohesion (SCC) is a fundamental process important for proper segregation of chromosomes. Defects in chromosome segregation lead to aneuploidy which is associated with multiple human diseases including neurological disorders, birth defects, infertility, and cancer. Inactivating mutations in the SCC establishment gene ESCO2, results in Robert syndrome (RBS), a developmental disease associated with microcephaly, craniofacial defects, growth retardation, limb deformities, mental retardation and other less penetrant phenotypes. Interestingly there is a wide spectrum of severity of phenotypes, ranging from prenatal lethal to asymptomatic adults – some displaying a cancer predisposition, influenced by genetic interaction of different genetic modifier genes. “Our research so far, indicates mechanistically that the amount of SCC dysfunction in a patient determines the severity of the disease. With that, we hypothesize that genes that modify in a positive or negative direction the amount of SCC dysfunction will influence the severity of the disease,” Parant said. The overall goal of this collaboration is to utilize unbiased whole genome CRISPR/Cas9 knockout technology to identify positive and negative modifier genes in a cell based system, and then validate that these modifier genes provide phenotypic modification of an animal model of RBS. Results from these studies will identify modifier genes that can be targets for therapeutic compounds that can restore SCC or be synthetic lethal with reduce SCC to treat a variety of human diseases. “I have been wanting to utilize an unbiased whole genome approach to identifying the modifier gene of the Roberts syndrome phenotype for a long time,” Parant said. “This pilot grant not only affords a financial means, but has established this interactive collaboration between the Cooper lab at Hudson Alpha and our research.”