Conserved loci on the X chromosome confer phosphate homeostasis in mice and humans

Several genes expressed in kidney and other tissues determine phosphate homeostasis in extracellular fluid. The major form of inherited hypophosphatemia in humans involves an X-linked locus (HPDR, Xp22.31-p21.3). It has two murine homologues (Hyp and Gy) which map to closely-linked but separate loci (crossover value 0.4%-0.8%). Both murine mutations impair Na(+)-phosphate cotransport in renal brush border membrane; an associated renal disorder of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) metabolism has been characterized in Hyp mice. Whereas experiments with cultured Hyp renal epithelium indicate that the gene is expressed in kidney, studies showing the development of the mutant renal phenotype in normal mice parabiosed to Hyp mice implicate a circulating factor; these findings can be reconciled if the humoral factor is of renal origin. The gene dose effect of HPDR, Hyp and Gy on serum phosphorus values is consistently deviant and heterozygotes resemble affected hemizygotes. The deviant effect is also seen on renal phosphate transport; all mutant females (Hyp/Hyp and Hyp/+) have similar phenotypes. On the other hand, there is a normal gene dose effect of HPDR in mineralized tissue; tooth PRATIO (pulp area/tooth area) values for heterozygotes are distributed between those for affected males and normals. The tooth data imply that the X chromosome locus is expressed in both renal and non-renal cells. The polypeptide product of the X chromosome gene(s) is still unknown.