DEFINING THE CELLULAR AND MOLECULAR BASIS OF LOWE SYNDROME FOR THE IDENTIFICATION AND VALIDATION OF TARGETS FOR PHARMACOLOGICAL INTERVENTION

Lowe syndrome is a rare X-linked genetic disease that is characterized by congenital cataracts, central hypotonia and renal tubular acidosis. Ocrl-1, the enzyme that is defective in Lowe syndrome, is a phosphoinositide 5-phosphatase which acts on important constituents of cell membranes, known as the phosphoinositides. The enzyme resides in two different cellular compartments: the Golgi complex and the endosomes. These compartments are an integral part of the main membrane trafficking pathways in the cell, and their function is fundamental to the establishment and maintenance of the organization of the cell itself. With this project, we intend to determine how Ocrl-1 contributes to the functioning of the Golgi complex and the endosome system. Our studies will improve our understanding of the cellular and metabolic basis of Lowe syndrome, and will lead to the identification and validation of pharmacological targets for its treatment. We will also be helped in this process by our analysis of the mutations to the OCRL-1 gene that have been identified in Italian patients, thanks to our collaboration with and support for, the Italian Lowe Syndrome Association (AISLO, http://aislo.negrisud.it), which we helped to establish in 2002.