title: X-linked hypophosphatemic rickets and the murine Hyp homologue.
abstract: Recent studies have reported the cloning of several sodium-dependent phosphate cotransport proteins from the apical membrane of proximal tubules of several species. The human proximal tubule apical sodium-phosphate cotransport protein maps to chromosome 5 in the 5q35 region, indicating that this gene is not a candidate for the genetic defect leading to X-linked hypophosphatemia (XLH). Studies in what is thought to be the murine XLH homologue, Hyp, also indicate that the proximal tubular phosphate cotransporter gene does not map to the X chromosome. In Hyp, message levels for the apical membrane sodium cotransport protein are reduced by approximately 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 sodium-dependent phosphate transport protein. Recent studies in the Hyp osteoblast have characterized the intrinsic abnormalities of the cell leading to the osteomalacia characteristic of both Hyp and XLH. These studies demonstrate that the Hyp osteoblast expresses normal rates of phosphate transport, but altered gluconeogenesis similar to the proximal tubule, and that there is an underphosphorylation of an important matrix protein, osteopontin. Since osteopontin is involved in matrix mineralization, defective posttranslational modification of the protein could be a factor in producing the osteomalacia of the Hyp. Other recent studies have demonstrated improved modalities of treatment for Hyp and potentially for XLH. These involve the use of phosphate and nonhypercalcemic analogues of 1 alpha,25-dihydroxyvitamin D3. 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.
authors.affiliation: Renal Division, Jewish Hospital of St. Louis at Washington, University Medical Center, Missouri 63110.
authors.forename: K A
authors.initials: KA
authors.lastname: Hruska
authors.forename: L
authors.initials: L
authors.lastname: Rifas
authors.forename: S L
authors.initials: SL
authors.lastname: Cheng
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: L
authors.initials: L
authors.lastname: Halstead
authors.forename: L
authors.initials: L
authors.lastname: Avioli
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D005943:Gluconeogenesis; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D053495:Osteopontin; D028044:Phosphate-Binding Proteins; D010710:Phosphates / Q000378:metabolism; D012795:Sialoglycoproteins / Q000096:biosynthesis; D014960:X Chromosome
chemical_list: D002352:Carrier Proteins; D028044:Phosphate-Binding Proteins; D010710:Phosphates; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D002117:Calcitriol