Funding outcome

Wasting phosphate in the urine usually occurs due to mutations in the PHEX gene. This causes the childhood disease rickets. This leads to poorly mineralized bones. However, a 9-year-old female with significantly elevated urine phosphate levels surprisingly lacked a mutation in PHEX, nor any of the other lesser-known genes causing this disorder. Furthermore, like patients with PHEX mutations, she had inappropriately increased levels of a hormone produced by bone cells, FGF23, which were responsible for her increased urinary phosphate excretion and consequently poorly mineralized bones. Sequencing the genes of the girl as well as those of her parents identified 9 new mutations, but only one in a gene expressed in bones - SVEP1. We hypothesize that SVEP1 regulates FGF23 production and prevents its excretion from bone cells. More specifically, we predict that in cells where SVEP1 expression is reduced, FGF23 production and release from bone cells will increase and in cells where SVEP1 expression is over-expressed, FGF23 levels will decrease. The cell lines with reduced SVEP1 expression will also demonstrate a reduced ability to mineralize bone. To test our hypothesis, we will use these different cell lines and measure the amount of FGF23 secreted, as well as gene expression and protein localization. Through this research, we hope to demonstrate that a mutation in SVEP1 increases FGF23 excretion and thus increase urine phosphate levels and rickets. This work will provide answers for clinicians and the patient's family regarding the cause of her disorder and also provide a valuable tool (i.e. cell lines) to test therapies on.