The X-linked Hyp and Gy mutations are murine homologues of X-linked hypophosphatemia (XLH), a dominant disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets, hypophosphatemia and decreased renal tubular maximum for Pi reabsorption relative to glomerular filtration rate (Tmp/GFR). In Hyp and Gy mice, the decrease in Tmp/GFR is associated with a reduction in renal brush-border membrane (BBM) Na(+)-Pi cotransport that can be ascribed to a decrease in renal-specific, Na(+)-Pi cotransporter (NPT2) mRNA and protein abundance. Although renal NPT2 gene expression is reduced in Hyp and Gy mice, the NPT2 gene does not map to the X chromosome. These findings exclude NPT2 as a candidate gene for murine and human X-linked hypophosphatemias and suggest that genes at the Hyp, Gy and XLH (HYP) loci are involved in regulation of NPT2 gene expression. Both Hyp and Gy mice respond to low Pi diet with an increase in BBM Na(+)-Pi cotransport, NPT2 mRNA and protein. The increase in NPT2 protein in Pi-depleted mice far exceeds the increase in NPT2 mRNA, suggesting that translational or post-translational mechanisms are involved in the adaptive process. NPT2 protein is localized to the apical surface of the proximal tubule, where immunostaining in both normal and Hyp mice is increased in response to low Pi diet. Pi-deprived Hyp and Gy mice fail to show an increase in Tmp/GFR, indicating that adaptation at the BBM is not sufficient for the overall increase in Tmp/GFR in response to low Pi diet.