ELUCIDATION OF THE MOLECULAR MECHANISM OF A DOMINANT FORM OF FAMILIAL EXUDATIVE VITREORETINOPATHY AND GENERATION OF CELL AND ANIMAL MODEL SYSTEMS TO EXPLORE THERAPEUTIC STRATEGIES

The exudative familial vitreoretinopathy (FEVR) is a rare genetic disease that alters retina biogenesis during embryonal development. Retina angiogenesis is affected: the network of arteries and veins is altered, and these are weaker and leaky, resulting in the production of exudate that frequently lead to retina detachment and blindeness. Recent studies have identified the most frequent gene and the protein causative of FEVR: the Frizzled4 gene (Fz4) that codes for a receptor protein normally expressed on the surface of retinal cells. This receptor is activated by the extracellular ligand protein Norrin and turns on an intracellular signalling pathway crucial for correct angiogenesis. A frequent and severe Fz4 mutation that results in the disease is dominant (Fz4-FEVR). The mutated protein has a different aminoacidic sequence at the carboxyterminus, it is not transported from the endoplasmic reticulum where is generated to the plasma membrane, and traps wild-type Fz4 intracellularly. Our preliminary results show that Fz4-FEVR has lost a sequence motif at the carboxyterminus to bind a protein complex, and that this complex plays a role in the transport between ER and Golgi complex of proteins bearing such motif. However, this finding does not explain yet why Fz4-FEVR is prevented to reach the plasma membrane: in other cases, the loss of the motif slowes down but does not block transport. This project has three main targets: to decipher the molecular mechanism by which Fz4-FEVR does not reach the cell surface, to generate cellular and animal models of this form of FEVR and to explore therapeutic strategies. The results of this project might have a general relevance because other genetic diseases are probably associated to mutated membrane proteins that have lost the carboxyterminal motif as Fz4-FEVR.