UNCOVERING THE ROLE OF SEDLIN IN THE PATHOGENESIS OF SPONDYLOEPIPHYSEAL DYSPLASIA TARDA (SEDT)

Spondyloepiphyseal dysplasia tarda is an X-linked genetic disorder that is characterized by disproportionate short stature, short neck and trunk, and barrel chest. It has been shown that mutations in the sedlin (SEDL) gene are responsible for the disease. SEDL is part of a multiprotein complex known as TRAPP. At present, it is thought that TRAPP functions in the transport of proteins within the cell and to the cell membrane. Such transport processes are fundamental for the well-being of the cell. Many inherited and acquired diseases are caused by impairment of the machinery that controls these processes, such as occurs in spondyloepiphyseal dysplasia tarda. However, the function of the SEDL gene itself is so far unknown. With the present project, we propose to uncover the function of SEDL and how its dysfunction leads to the development of spondyloepiphyseal dysplasia tarda. Interestingly, both the SEDL gene and the TRAPP complex have been conserved throughout evolution. This gives us the opportunity to use model organisms to uncover the function of SEDL. We will perform studies in yeast as a model organism in parallel with mammalian cells to define the processes that are impaired upon SEDL dysfunction. Furthermore, we will search for other molecules that interact with the SEDL protein to better define its function. These findings will be used to analyse similar processes in chondrocytes, the cells that are involved in bone formation and that are affected by SEDL mutations. Finally, we will introduce mutations into a vertebrate model organism, the zebrafish, to understand how SEDL mutations lead to bone abnormalities in vivo. These approaches promise to lead to a significant advance in our understanding of the function of the SEDL gene and how its dysfunction leads to spondyloepiphyseal dysplasia tarda. Such an understanding of spondyloepiphyseal dysplasia tarda will contribute to developing new strategies for its management.