Dissecting the molecular mechanisms underlying endocytic dysfunctions induced by mutations in OCRL and CLC5 to identify correctors for Lowe syndrome and Dent disease

Lowe syndrome is a rare X-linked genetic disease that is characterized by congenital cataracts, central hypotonia and renal Fanconi syndrome. In Fanconi syndrome, glucose, proteins, salts (including phosphate and bicarbonate) are passed into the urine, instead of being reabsorbed, with serious systemic consequences such as acidosis and bone fragility. The average life expectance in Lowe syndrome is on average around 30 years with end-stage renal failure being the main cause of death. Fanconi syndrome is due to an impaired function of the proximal renal tubules, which are the first to process the renal ultrafiltrate and have a very high absorptive capacity. Dent disease is also a rare X-linked genetic disease (previously reported as X-linked recessive nephrolithiasi) which shares with Lowe syndrome only the Fanconi syndrome, but which has no involvement of central nervous system or of the eyes. Progression to end-stage renal failure occurs between the 3rd and 5th decade in the majority of Dent patients. There is no specific therapy for Lowe syndrome or for Dent disease. Mutations in the Ocrl-1 gene can give rise to Lowe syndrome or to Dent disease, while mutations in the CLCN5 gene give rise to Dent disease. The product of the Ocrl-1 gene is an enzyme that acts on important constituents of cell membranes, known as phosphoinositides, while the product of CLCN5 gene is a chloride channel. The exact mechanisms by which mutations in these two genes cause impairment of the function of the renal proximal tubule are not known and represent the main focus of the project. The final aim of the project is to exploit knowledge of the function of these two gene products to search for pharmacological correctors. The positive hits will be then tested in the mouse model of tubulopathy induced by OCRL depletion. This will represent a first step to move towards a pharmacological intervention in Lowe syndrome and Dent disease.