Funding outcome

The Alexander laboratory identified a 9-year-old female with the signs and symptoms of hereditary hypophosphatemic rickets (HHR) including low blood phosphate levels, excessive urinary excretion of phosphate, bone pain and an elevated FGF23 plasma level. In this disease bone tissue secretes an excessive amount of the FGF23 hormone into the blood. This hormone in turn stimulates increased phosphate excretion in the urine leading to a low blood phosphate level. Consequently, the body lacks sufficient phosphate for bone mineralization, energy for movement and basic metabolic activity. Interestingly, DNA analysis failed to detect a mutation in any of the genes known to cause HHR but did detect a SVEP1 mutation. This gene is only expressed in bone, where FGF23 is made. Treatment for these patients is mainly supportive with limited therapeutic options due to the limited understanding of HHR. Our work seeks to understand how SVEP1 affects FGF23 levels and secretion from bone cells. Unfortunately, deletion of the SVEP1 gene in mice is lethal. Therefore we will introduce the SVEP1 mutation in a bone cell model and make a fish with the mutation to study FGF23 levels (fish lacking SVEP1 survive). Creating these models will facilitate the investigation of the role that SVEP1 plays in FGF23 formation and release from bone cells and allow us to test new potential therapeutics for persons with HHR.