X-LINKED HYPOPHOSPHATEMIC RICKETS AND THE MURINE HYP HOMOLOG

Recent studies have reported the cloning of several sodium-dependent p hosphate cotransport proteins from the apical membrane of proximal tub ules of several species. The human proximal tubule apical sodium-phosp hate cotransport protein maps to chromosome 5 in the 5q35 region, indi cating that this gene is not a candidate for the genetic defect leadin g to X-Linked hypophosphatemia (XLH). Studies in what is thought to be the murine XLH homologue, Hyp, also indicate that the proximal tubula r phosphate cotransporter gene does not map to the X chromosome. In Hy p, message levels for the apical membrane sodium cotransport protein a re reduced by similar to 50%, similar to the reductions in the apical membrane protein levels of the transporter. This indicates a potential transcriptional defect in Hyp, leading to underexpression of the sodi um-dependent phosphate transport protein. Recent studies in the Hyp os teoblast have characterized the intrinsic abnormalities of the cell le ading to the osteomalacia characteristic of both Hyp and XLH. These st udies demonstrate that the Hyp osteoblast expresses normal rates of ph osphate transport, but altered gluconeogenesis similar to the proximal tubule, and that there is an underphosphorylation of an important mat rix protein, osteopontin. Since osteopontin is involved in matrix mine ralization, defective posttranslational modification of the protein co uld be a factor in producing the osteomalacia of the Hyp. Other recent studies have demonstrated improved modalities of treatment for Hyp an d potentially for XLH. These involve the use of phosphate and nonhyper calcemic analogues of 1 alpha,25-dihydroxyvitamin D-3. Thus, although the detection of the genetic defect producing XLH and Hyp is awaited, significant advances in the characterization of the phenotype and the bone abnormalities continue.