Grant: Project Grant

Hereditary hypophosphatemic rickets is a group of disorders that is characterized by bony abnormalities, that can result in pain and deformity throughout life. The primary issue for these patients is they pee too much phosphate, which lowers blood phosphate levels (i.e. hypophosphatemia). Phosphate is a critical component of bone and when it is not at adequate levels in the blood, bone fails to form properly. Despite recent advances, treatment is largely ineffective for most, and patients suffer from life-long bony deformations and pain. We identified a new genetic variation in a large cohort of Heutterites from Alberta and Saskatchewan in a kidney phosphate transporter, SLC34A3, causing hypophosphatemic rickets. When two copies of the variation is present the patients have a disorder called hereditary hypophosphatemic rickets with hypercalciuria and have both bony abnormalities and kidney stones. This genetic variation occurs commonly in this population (1:40 people are carriers). Our preliminary data and data from others supports a partial phenotype in people who have one copy of their DNA affected including osteoarthritis and kidney stones. We will study this unique cohort of patients and their families to understand how genetic variations in this kidney phosphate absorbing gene contributes to these common diseases, osteoporosis and kidney stones. Given that variations in this gene contribute to osteoporosis and kidney stones in the general population, we will model this mutation in cell culture and an animal model to dissect out how it increases phosphate loss in the urine. We will also use these models to identify novel treatments for these patients and hopefully others with disease due to genetic variations in this gene. Our results will help to explain why patients with genetic variations in SLC34A3 excrete more phosphate in their urine and enable us to design specific targeted treatments for common diseases that occur due to genetic variations in SLC34A3.