IMPC: Analysis of the novel craniocardiac malformation gene Rapgef5

Birth defects are the major cause of infant mortality in the UK and in Europe. Of these, congenital craniofacial and cardiac malformations are amongst the most common with heart anomalies as the leading cause of infant mortality and morbidity. If we are to improve patient well being, we must identify and understand the genetic causes of birth defects as a critical first step towards improved screening, genetic counselling and personalised treatment strategies. Having identified human RAPGEF5 in patients with heart anomalies, we now need to establish a mammalian model, in order to better understand the underlying biological roles for the gene. This pump-priming project will establish an IMPC-generated mouse model Rapgef5. In addition to its role as a birth defect gene, Rapgef5 also seems to be important in the Wnt signalling pathway, which is associated with aging, and with disorders such as cancer and neurodegeneration. Therefore, establishment of this mouse model may provide us with a tool to understand human birth defects as well as important signalling processes that occur in human disease.

RAPGEF5 is a newly identified candidate birth defect gene, originally identified in a heterotaxy patient. Heterotaxy is a disorder of left-right development and is associated with a severe subset of congenital heart anomalies. Previous data using the frog Xenopus confirmed a requirement for RAPGEF5 in LR development, organ situs and craniofacial development. Establishing a regulator of nuclear accumulation of beta-catenin would transform our understanding of the Wnt pathway and facilitate the development of treatments for diseases such as cancer and cardiac ischemia. In order to investigate this promising congenital disease gene, we need to build on our work by using mammalian systems, which better represent human genetics, development and cardiac anatomy. In particular, we take advantage of powerful murine genetics and state of the art cell culture techniques and reagents available in the lab. We anticipate that this project will provide us with the tools to understand the role of RAPGEF5 in development as well as the biochemical role of RAPGEF5 and associated RAP proteins in signal transduction.