The original goal of this research was to define the physiological roles of two genes on the human X-chromosome that importantly control mineral homeostasis. Clinical studies of patients with heritable disorders mapped to the two loci of interest show that one gene is essential for embryogenesis of the parathyroid glands (and thereby maintenance of extracellular fluid calcium levels), and the other gene controls blood phosphate concentrations and the bioactivation of vitamin D at the kidney level. Specifically, the genetic defects cause X-linked recessive idiopathic hypoparathyroidism (XHPT) and X-linked hypophosphatemia (XLH). The XHPT locus has been narrowed to a 1.5 Mb region in a unique, large kindred and three candidate genes have been identified. The gene involved in XLH is called PEX or PHEX (phosphate-regulating endopeptidase on the X-chromosome), but regulation of its expression and the function of the encoded protein are not understood. PEX seems to degrade a phosphaturic hormone designated phosphatonin. In response to past evaluation comments, this twice amended application has omitted XLH investigations. For XHPT, the Specific Aims of this proposal focus on isolation and characterization of candidate genes, identification of the precise causative mutation (and corresponding gene), and initiation of characterization of the biological role of the XHPT gene.
