Understudied rare disease genes that cause heterotaxy in zebrafish

About This Grant

Summary Rare diseases collectively affect approximately 30 million people in the U.S., posing a significant health and economic burden. Despite their impact, the genetic and molecular bases of many rare diseases remain poorly understood, hindering the development of effective diagnostics and therapies. This proposal focuses on elucidating the functions of a subset of understudied proteins associated with rare diseases, identified in NIH PAR-25-122, that may play critical roles in left-right (LR) patterning during embryonic development. Disruptions in LR patterning underlie heterotaxy syndrome, a rare congenital disorder characterized by mispositioned internal organs and often severe cardiac malformations. Knowledge gained on how these proteins function in LR patterning can then be leveraged to understand how the protein may function to produce rare disease phenotypes in other tissues and will identify genes that should be evaluated as causative for Heterotaxy in humans. Building on extensive expertise in zebrafish models of LR development, the project aims to (1) assess the role of candidate proteins in LR patterning using antisense and CRISPR-based approaches, (2) generate targeted mutations in genes affecting LR development, and (3) develop transgenic zebrafish lines and antibodies to enable functional studies and lay the groundwork for future drug screening efforts. Zebrafish provide a powerful in vivo system to investigate gene function and conduct high-throughput drug screens. The proposed research will advance our understanding of rare disease gene function in LR patterning and establish essential tools to support therapeutic discovery in future proposals.