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

Abstract

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.

Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

“…Mutations in homologous genes on the human (HYP) and mouse (Hyp) X chromosomes are responsible for X-linked hypophosphatemia, a disorder in renal Pi reabsorption characterized by rachitic bone disease ( 1,5). In the present study, we demonstrate that the specific defect in Na '-dependent Pi transport in the renal brush border membrane of Hyp mice (6,7,10) is associated with a specific decrease in the renal abundance of Na+-Pi cotransporter mRNA and protein.…”

“…Like their human counterparts, Hyp mice are characterized by rachitic bone disease, hypophosphatemia, and impaired renal reabsorption of filtered phosphate (Pi)' (1,2). In both mouse (3) and humans (4), the mutation maps to one offive highly conserved regions on the X chromosome (5). Neither the gene nor its product have been identified.…”

Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3

“…In this regard, it is important to consider the results of studies in humans and mice with X-linked hypophosphatemia, a dominant disorder of P i homeostasis associated with impaired skeletal mineralization and caused by inactivating mutations in the PHEX/Phex gene (37). The disease phenotype is as severe in affected males and females (31,43), as well as in female mice carrying either one or two copies of the mutant allele (31, 32, 35). These findings, which provide evidence for haploinsufficiency of PHEX (41), indicate that PHEX protein produced from the wild-type allele in affected heterozygous females does not reach the threshold level necessary for normal function and that the disease phenotype is manifest in the face of a 50% decrease in PHEX expression.…”

Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice.

“…It is a dominant disorder of phosphate homeostasis characterized by rachitic and osteomalacic bone disease, short stature, hypophosphatemia, and renal defects in phosphate reabsorption and vitamin D metabolism (2). Much of our knowledge of the human disease is derived from studies of the murine Hyp mutation (2)(3)(4)(5), which maps to a region of the mouse X chromosome that is syntenic to the XLH ( HYP ) locus on the human X chromosome (6). We demonstrated that Hyp mice have a specific defect in phosphate transport across the renal brush border membrane that is associated with a decrease in high affinity Na ϩ -phosphate cotransport V max (7) and can be ascribed to a decrease in renal abundance of type II Na ϩ -phosphate cotransporter ( Npt2 ) mRNA and immunoreactive protein (8).…”