X-linked hypophosphataemia: a homologous disorder in humans and mice

X-linked hypophosphatemia is an inherited disorder of phosphate (Pi) homeos tasis characterized by growth retardation, rickets and osteomalacia, hypoph osphataemia, and aberrant renal Pi reabsorption and vitamin D metabolism. S tudies in murine Hyp and Gy homologues have identified a specific defect in Na+-Pi cotransport at the brush border membrane, abnormal regulation of 1, 25-dihydroxyvitamin D-3 (1,25(OH)(2)D) synthesis and degradation, and an in trinsic defect in bone mineralization. The mutant gene has been identified in XLH patients, by positional cloning, and in Hyp and Gy mice, and was des ignated PHEX/Phex to signify a PHosphate-regulating gene with homology to E ndopeptidases on the X chromosome. PHEX/Phex is expressed in bones and teet h but not in kidney and efforts are under way to elucidate how loss of PHEX /Phex function elicits the mutant phenotype. Based on its homology to endop eptidases, it is postulated that PHEX/Phex is involved in the activation or inactivation of a peptide hormone(s) which plays a key role in the regulat ion of bone mineralization, renal Pi handling and vitamin D metabolism.