ROLE OF GOLGI MATRIX AND TRAPP PROTEINS IN ENDOPLASMIC RETICULUM TO GOLGI MEMBRANE TRAFFICKING AND IN THE PATHOGENESIS OF SPONDYLOEPIPHYSEAL DYSPLASIA TARDA (SEDL)

Spondyloepiphyseal dysplasia tarda (SEDL) is an X-linked genetic disorder characterized by disproportionate short stature, short neck and trunk, and barrel chest. Recently, it has been found that mutations in the SEDL gene are responsible for the disease. SEDL encodes a 104 aa protein, named sedlin. Sedlin is a component of a multiprotein complex, TRAPP. The fuctional role of TRAPP in human cells is unknown. However, the TRAPP complex in yeast is known to be important in the transport of membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. This is the first and a very important transport step for proteins that have to be transported to the cell membrane or outside the cell (i.e. secreted). Many inherited and acquired diseases, such as cystic fibrosis, Alzeheimer's disease, and some forms of hemofilia, are caused by impairments in the ER-to-Golgi transport of important factors. With the present project we propose to study the role of sedlin in the ER-to-Golgi transport of proteins that are important for the normal development of bone and cartilage tissues, the altered secretion of which might cause SEDL. Furthermore, we will study the exact intracellular localization of sedlin, as well as its interplay with factors known to be involved in regulating ER-to-Golgi transport, such as the Golgi matrix proteins. We will adopt an approach that will allow us to study the dynamics of the Golgi matrix proteins in living cells. Understanding the role of sedlin in the secretory pathway and its interplay with Golgi matrix proteins will be an important step forward in the comprehension of the molecular mechanism of SEDL and will contribute to the developing of new strategies for its management.