Grant: Project Grant

Understanding how genes impact physical traits is a central objective in human genetics, and this knowledge forms the basis for precision medicine in treating genetic disorders. To get a better understanding, we need to know how genetic differences lead to different traits. However, this question becomes challenging when it is related to genes encoding proteins that bind RNA because these proteins have complex functions and are dynamically regulated in a context-dependent manner. Even a single RNA-binding protein may have multiple roles in RNA regulation in different subcellular compartments, ranging from RNA biogenesis in the nucleus to protein synthesis in the cytoplasm. Given their essential roles, the malfunction of RNA-binding proteins is known to cause many human diseases. At the same time, their complexity also makes it difficult to interpret the pathological relevance of variants in such genes and predict their functional consequences. Filling these knowledge gaps requires a deeper understanding of RNA-binding proteins and the mechanisms of how they are regulated and function. This study will look into these issues, asking how pathological variants identified in a group of patients with various traits affect an RNA-binding protein and brain development and function. We plan to use human cell and animal models to address the underlying mechanisms that can connect these genetic differences to phenotypic traits. This study will help us better understand the relationships between genotype and phenotype related to RNA-binding proteins and uncover the mechanistic basis of a group of rare neurodevelopmental disorders.