Defining the cellular and molecular basis of the Spondyloepiphyseal Dysplasia Tarda and identification of targets for pharmacological intervention

Spondyloepiphyseal dysplasia tarda is an X-linked disorder that is characterized by disproportionate short stature, short neck and trunk, barrel chest, and premature osteoarthritis that manifests in childhood with the usual age of presentation being after the first decade of life. It has been shown that mutations in the sedlin (SEDL) gene are responsible for the disease. Presently, there is no specific therapy for this condition. SEDT appears to be due to a defect in the formation of cartilage possibly linked to an inability of chondrocytes (the cells that continually divide and lay down cartilage matrix during development) to properly secrete components required for bone formation. However, the function of SEDL in this process is so far unknown. Our preliminary data point to a role for SEDL in the secretion of one of the most abundant proteins of the cartilage matrix, called type II procollagen. Within the present project, we propose to uncover how SEDL defects leads to the development of SEDT. We will use approaches in mammalian and yeast cells (since sedlin is conserved in yeast) to define the processes that are impaired upon SEDL dysfunction and to identify possible drugs and genetic correctors. Additionally, we will analyze the consequences of disrupting the function of the sedlin protein in a vertebrate animal model. In addition we will test the capacity of any drug and genetic correctors identified in cell studies to overcome defects arising from SEDL disruption in the animal model. These correctors could provide leads for future therapeutic intervention.