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Endocrinology Vol. 144, No. 8 3463-3468
Copyright © 2003 by The Endocrine Society

Disordered Regulation of Renal 25-Hydroxyvitamin D-1{alpha}-Hydroxylase Gene Expression by Phosphorus in X-Linked Hypophosphatemic (Hyp) Mice

Nasreen Azam, Martin Y. H. Zhang, Xuemei Wang, Harriet S. Tenenhouse and Anthony A. Portale

Department of Pediatrics (N.A., M.Y.H.Z., X.W., A.A.P.), University of California San Francisco, San Francisco, California 94143; and Department of Pediatrics and Human Genetics (H.S.T.), McGill University and Montreal Children’s Hospital Research Institute, Montréal, Québec H3H 1P3, Canada

Address all correspondence and requests for reprints to: Anthony A. Portale, M.D., University of California San Francisco, 533 Parnassus Avenue, Room U-585, San Francisco, California 94143-0748. E-mail: aportale{at}peds.ucsf.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
X-linked hypophosphatemic (Hyp) mice exhibit hypophosphatemia, impaired renal phosphate reabsorption, defective skeletal mineralization, and disordered regulation of vitamin D metabolism: In Hyp mice, restriction of dietary phosphorus induces a decrease in serum concentration of 1,25-dihydroxyvitamin D and renal activity of 25-hydroxyvitamin D-1{alpha}-hydroxylase (1{alpha}-hydroxylase), and induces an increase in renal activity of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase). In contrast, in wild-type mice, phosphorus restriction stimulates renal 1{alpha}-hydroxylase gene expression and suppresses that of 24-hydroxylase. To determine the molecular basis for the disordered regulation of vitamin D metabolism in Hyp mice, we determined renal mitochondrial 1{alpha}-hydroxylase activity and the renal abundance of P450c1{alpha} and P450c24 mRNA in wild-type and Hyp mice fed either control, low-, or high-phosphorus diets for 5 d. In wild-type mice, phosphorus restriction increased 1{alpha}-hydroxylase activity and P450c1{alpha} mRNA expression by 6-fold and 3-fold, respectively, whereas in the Hyp strain the same diet induced changes of similar magnitude but opposite in direction. Phosphorus supplementation was without effect in wild-type mice, whereas in Hyp mice the same diet induced 3-fold and 2-fold increases, respectively, in enzyme activity and P450c1{alpha} mRNA abundance. In wild-type mice, both renal 1{alpha}-hydroxylase activity and P450c1{alpha} mRNA abundance varied inversely and significantly with serum phosphorus concentrations, whereas in Hyp mice the relationship between both renal parameters and serum phosphorus concentration was direct. In Hyp mice, phosphorus restriction induced a significant increase in renal P450c24 mRNA abundance, in contrast to the lack of effect observed in wild-type mice. The present findings demonstrate that regulation of both the P450c1{alpha} and P45024 genes by phosphorus is disordered in Hyp mice at the level of renal 1{alpha}-hydroxylase activity and renal P450c1{alpha} and P450c24 mRNA expression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
X-LINKED HYPOPHOSPHATEMIA (XLH) (OMIM 307800, 307810) is the most prevalent form of inherited rickets in humans, with an incidence of 1 in 20,000 individuals (1). It is a dominant disorder characterized by hypophosphatemia secondary to renal phosphate wasting, abnormal regulation of renal metabolism of vitamin D, rickets and osteomalacia, growth failure, and resistance to vitamin D therapy. The gene responsible for XLH was identified by positional cloning and designated PHEX (formerly PEX) to depict a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (2). The 171 mutations in the PHEX gene that have been identified to date in patients with XLH are catalogued in a locus-specific database (3) (www.phexdb.mcgill.ca). The mutations, which are scattered throughout the gene, include deletions, splice junction and frameshift mutations, duplications, insertions, and missense and nonsense mutations, and are consistent with loss of function of the PHEX protein.

The PHEX protein bears homology to the M13 family of zinc metallopeptidases, which are type II integral membrane glycoproteins involved in the activation or inactivation of a variety of peptide hormones (4). PHEX mRNA and protein are expressed predominately in bone and teeth (5, 6, 7, 8, 9) and have not been detected in kidney (5, 6, 7, 10). However, the nature of the PHEX substrate(s) and its (their) role in regulation of phosphorus homeostasis, vitamin D metabolism, and skeletal mineralization, are unknown. Moreover, the mechanism whereby loss of PHEX function gives rise to the clinical and biochemical phenotype of XLH is not understood.

Abnormal regulation of vitamin D metabolism is characteristic of XLH. In patients with XLH, serum concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D] are nominally within the normal range (11, 12, 13). However, such values are inappropriately low given the attendant hypophosphatemia, and serum 1,25(OH)2D concentrations fail to increase with restriction of dietary phosphorus intake (14). By contrast in healthy subjects, hypophosphatemia, induced by phosphorus restriction, induces a substantial increase in the serum concentration and production rate of 1,25OH)2D (14, 15, 16, 17, 18).

Regulation of vitamin D metabolism is similarly disordered in the X-linked Hyp mouse, which exhibits the phenotypic features of XLH, including hypophosphatemia secondary to impaired renal phosphate reabsorption and defective skeletal mineralization (19, 20) and harbors a large (18-kb) 3' deletion in the Phex gene (5). In Hyp mice, the serum concentration of 1,25(OH)2D is not different from that in normal littermates and, therefore, is inappropriately low for the degree of hypophosphatemia (21, 22, 23). Renal activity of 25-hydroxyvitamin D-1{alpha}-hydroxylase (1{alpha}-hydroxylase or P450c1{alpha}), the enzyme that catalyzes the conversion of 25-hydroxyvitamin D (25OHD) to 1,25(OH)2D, also is inappropriately low for the degree of hypophosphatemia (22), and dietary phosphorus restriction induces a paradoxical decrease in both serum concentration of 1,25(OH)2D (21, 23) and renal 1{alpha}-hydroxylase activity (24). In addition, the stimulation of renal 1{alpha}-hydroxylase activity induced by either a low calcium diet (25, 26) or the administration of PTH or cAMP (27, 28) is blunted in Hyp mice when compared with that in wild-type mice, suggesting the presence of a generalized disorder in regulation of renal 1{alpha}-hydroxylase in XLH.

The regulation of 25OHD-24-hydroxylase (24-hydroxylase or P450c24), the enzyme that initiates the catabolism of 1,25(OH)2D via the C-24 oxidation pathway to calcitroic acid in kidney and vitamin D target tissues, also is abnormal in Hyp mice. Renal enzyme activity is 2-fold higher in Hyp mice than in wild-type littermates (29) and is paradoxically increased further with dietary phosphorus restriction (23). Indeed, it was suggested that, in Hyp mice, increased renal catabolism of 1,25(OH)2D via the C-24 oxidation pathway leads to reduced availability of this hormone and thereby contributes to the phenotype of the disorder (23, 29).

The molecular basis for the disordered regulation of both 1,25(OH)2D synthesis and degradation in Hyp mice is unknown. In the present study, we sought to characterize the effects of manipulation of dietary phosphorus on renal 1{alpha}-hydroxylase activity and P450c1{alpha} and P450c24 mRNA expression in Hyp mice and their normal littermates.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice
Animals were obtained by breeding C57BL/6J Hyp/+ females with C57BL/6J +/Y males at McGill University. The original breeding pairs were purchased from The Jackson Laboratory (Bar Harbor, ME). We studied mutant Hyp/Y and wild-type +/Y male mice at 200 ± 5 d of age. To determine the effect of dietary phosphorus intake on renal 1{alpha}-hydroxylase activity and renal P450c1{alpha} and P450c24 mRNA expression, animals first were fed a vitamin D-replete control diet containing 1.0% phosphorus and 1.0% calcium for 5 d (test diet TD 86129, Harlan Teklad, Madison, WI). One group continued to receive the control diet, and two other groups received otherwise identical diets containing either 0.02% phosphorus (Teklad 86128) or 1.65% phosphorus (Teklad 88345) for 5 more days. Animals were anesthetized with pentobarbital, and blood was drawn by cardiac puncture for determination of serum phosphorus concentration, using a kit from Stanbio Laboratories (San Antonio, TX). The kidneys were removed; one kidney was rapidly frozen in liquid nitrogen for subsequent extraction of RNA and the other placed in homogenizing medium at 4 C for isolation of renal mitochondria. All procedures were approved by the Committee on Animal Research, University of California San Francisco.

Renal mitochondrial 1{alpha}-hydroxylase activity
Renal mitochondrial 1{alpha}-hydroxylase activity was determined as described (30). Briefly, renal mitochondria were isolated by the method of Vieth and Fraser (31). Duplicate 1-ml aliquots of mitochondrial protein (2.0–3.0 mg/ml) were suspended in buffer and incubated with 500 nM chromatographically purified 25OHD3 at 24 C for 15 min. The reaction was stopped by addition of 1.0 ml acetonitrile, lipid was extracted, and 1,25(OH)2D was isolated from the lipid extract by sequential C-18 and silica column chromatography and quantitated in duplicate by radioreceptor assay.

Renal 1{alpha}- and 24-hydroxylase mRNA expression
The abundance of renal P450c1{alpha} and P450c24 mRNA, relative to ß-actin mRNA, was quantitated by ribonuclease protection assay as described (30, 32), using the HybSpeed RPA assay kit (Ambion, Austin, TX). P450c1{alpha} and P450c24 riboprobes were derived from unique regions of their respective cDNA sequences as described (30, 32). Total RNA, isolated from kidneys using the TRIzol reagent (Life Technologies/ Invitrogen, Carlsbad, CA), was hybridized with the appropriate riboprobes (5 x 105 cpm) at 68 C for 10 min, and treated with ribonuclease A (5 U/ml) and T1 (200 U/ml) at 37 C for 30 min. The remaining protected RNA fragments were precipitated, denatured, and resolved on a denaturing 5% acrylamide/8 M urea gel. The gel was dried and exposed to a PhosphorImager screen (Molecular Dynamics, Sunnyvale, CA) for quantitation. Results are expressed as the ratio of P450c1{alpha} or P450c24 mRNA to ß-actin mRNA.

Statistical analysis
Data are expressed as mean ± SEM. The significance of differences was analyzed using two factor (mouse strain and dietary phosphorus) ANOVA. The relationship between variables was assessed using the Pearson product-moment correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Renal 1{alpha}-hydroxylase activity
To determine the effect of dietary phosphorus on renal mitochondrial 1{alpha}-hydroxylase activity, wild-type and Hyp mice were fed either control (1.0%), low- (0.02%), or high- (1.6%) phosphorus diet for 5 d. In wild-type mice fed the low-phosphorus diet, renal mitochondrial 1{alpha}-hydroxylase activity increased to values 6-fold higher than those in mice fed the control diet (P < 0.01) (Fig. 1AGo). In wild-type mice fed the high-phosphorus diet, renal 1{alpha}-hydroxylase activity did not change significantly. In contrast, in Hyp mice fed the low-phosphorus diet, renal 1{alpha}-hydroxylase activity decreased to values 6-fold lower than those in Hyp mice fed the control diet (P < 0.01) (Fig. 1AGo). In Hyp mice fed the high-phosphorus diet, enzyme activity increased 3-fold, relative to that in mice fed the control diet. For each of the three phosphorus intakes, 1{alpha}-hydroxylase activity in Hyp mice was significantly different from that in wild-type mice (P < 0.05) (Fig. 1AGo).



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  		FIG. 1. Effect of dietary phosphorus on renal mitochondrial 1{alpha}-hydroxylase activity (A) and renal P450c1{alpha} mRNA abundance (B and C) in wild-type (clear bars) and Hyp (hatched bars) mice. Mice were fed either the control (1%), low- (0.02%), or high- (1.6%) phosphorus diet for 5 d. A, Renal mitochondria were prepared and incubated with 25OHD3 to determine 1{alpha}-hydroxylase activity as described in Materials and Methods. B and C, Total RNA was isolated from kidney and the abundance of P450c1{alpha} mRNA, relative to ß-actin mRNA, was quantitated by ribonuclease protection assay as described in Materials and Methods. B, Representative data from three wild-type and three Hyp mice fed either control (middle panel), low- (left panel), or high- (right panel) phosphorus diet for 5 d. C, Bars depict mean ± SEM. *, Compared with the 1% phosphorus diet, within each species, P < 0.05. #, Compared with wild-type animals, within each diet group, P < 0.05.

 
Serum phosphorus concentration
The serum phosphorus concentration was significantly lower in Hyp mice than in wild-type mice on each of the three phosphorus intakes (P < 0.001) (Table 1Go). In wild-type mice, the serum phosphorus concentration decreased significantly on the low-phosphorus diet but did not change significantly on the high-phosphorus diet, compared with values on the control diet (Table 1Go). In Hyp mice, the serum phosphorus concentration also decreased significantly on the low-phosphorus diet and increased significantly on the high-phosphorus diet, compared with values on the control diet (Table 1Go).


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  		TABLE 1. Effect of dietary phosphorus on serum phosphorus concentration in wild-type and Hyp mice

 
We examined the relationship between renal 1{alpha}-hydroxylase activity and serum phosphorus concentration in wild-type and Hyp mice fed either the control, low-, or high-phosphorus diet. In wild-type mice, 1{alpha}-hydroxylase activity varied inversely and significantly with serum phosphorus concentration (R= -0.74, P < 0.01) (Fig. 2AGo), whereas, in Hyp mice, there was a significant direct relationship between these two parameters (R= +0.71, P < 0.01) (Fig. 2AGo).



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  		FIG. 2. Relationship between serum phosphorus concentration and renal 1{alpha}-hydroxylase activity (A) and renal P450c1{alpha} mRNA abundance (B) in wild-type and Hyp mice. Mice were fed control (1%), low- (0.02%), or high- (1.6%) phosphorus diet for 5-fold. The serum phosphorus concentration, renal 1{alpha}-hydroxylase activity, and P450c1{alpha} mRNA relative to ß-actin mRNA, were determined as described in Materials and Methods. Each point depicts data from individual wild-type (WT, {bullet}) and Hyp {circ}) mice. Renal P450c1{alpha} mRNA abundance in WT mice varied inversely with serum phosphorus concentration (R = -0.80, P < 0.01) and in Hyp mice varied directly with serum phosphorus concentration (R = +0.77, P < 0.01).

 
Renal P450c1{alpha} mRNA abundance
In wild-type mice, the low-phosphorus diet induced a 3-fold increase in renal P450c1{alpha} mRNA abundance, whereas the high-phosphorus diet had no significantly effect on transcript abundance, when compared with values in wild-type mice fed the control diet (Fig. 1Go, B and C). In contrast, in Hyp mice, the low-phosphorus diet induced a 5-fold decrease in renal P450c1{alpha} mRNA abundance, and the high-phosphorus diet induced a 1.8-fold increase in transcript abundance, when compared with values in Hyp mice fed the control diet (Fig. 1Go, B and C). On each of the three phosphorus intakes, renal P450c1{alpha} mRNA abundance in Hyp mice was significantly different from that in wild-type mice (P < 0.01) (Fig. 1CGo).

We examined the relationship between renal P450c1{alpha} mRNA abundance and serum phosphorus concentration in wild-type and Hyp mice fed either control, low-, or high-phosphorus diet. In wild-type mice, renal P450c1{alpha} mRNA abundance varied inversely and significantly with serum phosphorus concentration (R= -0.80, P < 0.01) (Fig. 2BGo), whereas in Hyp mice, there was a significant direct relationship between these two parameters (R= +0.77, P < 0.01) (Fig. 2BGo).

In both wild-type and Hyp mice, renal P450c1{alpha} mRNA abundance varied directly and significantly with renal 1{alpha}-hydroxylase activity (P < 0.001) (Fig. 3Go). The slopes of the relationship for the two mouse strains were not significantly different (Fig. 3Go).



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  		FIG. 3. Relationship between renal P450c1{alpha} mRNA abundance and 1{alpha}-hydroxylase activity in wild-type (R = 0.71, P < 0.001) and Hyp (R= 0.81, P < 0.001) mice fed control, low-, or high-phosphorus diet for 5 d. For details, see legend to Figs. 1Go and 2Go. The slopes of the two regressions do not differ significantly from each other.

 
Renal P450c24 mRNA abundance
In wild-type mice, renal P450c24 mRNA abundance was not significantly different on the low-phosphorus diet and was significantly increased on the high-phosphorus diet (P < 0.05), when compared with values in wild-type mice fed the control diet (Fig. 4Go). In contrast, in Hyp mice, renal P450c24 mRNA abundance was significantly higher on the low-phosphorus diet (P < 0.05) and not significantly different on the high-phosphorus diet, when compared with values in Hyp mice fed the control diet (Fig. 4Go). Renal P450c24 mRNA abundance in Hyp mice was significantly different from that in wild-type mice on the low-phosphorus diet, but there were no differences between groups on the high-phosphorus or the control diet (P < 0.01) (Fig. 4Go).



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  		FIG. 4. Effect of dietary phosphorus on renal P450c24 mRNA abundance. Mice were fed control (1%), low- (0.02%), or high- (1.6%) phosphorus diet for 5 d. Total RNA was isolated from kidney and the abundance of P450c24 mRNA, relative to ß-actin mRNA, was quantitated by ribonuclease protection assay as described in Materials and Methods. A, Representative data from three wild-type and three Hyp mice fed either control (middle panel), low- (left panel), or high-phosphorus (right panel) diet for 5 d. B, Bars depict mean ± SEM. *, Compared with the 1% phosphorus diet, within each species, P < 0.05. #, Compared with wild-type animals, within each diet group, P < 0.05.

 
We examined the relationship between renal P450c24 mRNA abundance and serum phosphorus concentration in wild-type and Hyp mice. In wild-type mice, renal P450c24 mRNA abundance varied directly and significantly with serum phosphorus concentration (R= +0.64, P < 0.01), whereas in Hyp mice, the relationship between these two parameters was inverse and significant (R= -0.46, P < 0.02).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrate that restriction of dietary phosphorus increases renal mitochondrial 1{alpha}-hydroxylase activity and mRNA expression in wild-type mice by 6-fold and 3-fold, respectively, consistent with previous reports (30, 32, 33), whereas the same dietary restriction in the mutant Hyp strain induces changes that are of similar magnitude but opposite in direction. In wild-type mice, both renal 1{alpha}-hydroxylase activity and mRNA abundance vary inversely and significantly with serum phosphorus concentrations (30), whereas in Hyp mice the relationship between both renal parameters and serum phosphorus concentration is direct. These relationships are strikingly similar to the relationships we previously observed between serum 1,25(OH)2D and serum phosphorus concentrations in wild-type and Hyp mice (23). Furthermore, in the present study we show that the values of renal 1{alpha}-hydroxylase activity in both wild-type and Hyp mice vary directly and significantly with those of P450c1{alpha} mRNA, despite the disordered regulation of renal 1,25(OH)2D production by phosphorus in the mutant strain. We report that the response of renal 1{alpha}-hydroxylase to supplementation of dietary phosphorus also differs in wild-type and Hyp mice. Feeding a high-phosphorus diet is without effect in wild-type mice, whereas in Hyp mice the same diet induced 3-fold and 2-fold increases, respectively, in renal enzyme activity and mRNA abundance.

We also demonstrate in Hyp mice that phosphorus restriction induces a significant increase in renal P450c24 mRNA abundance. These findings are in agreement with the previous demonstration of increased 24-hydroxylase mRNA (34, 35) and enzyme activity (23) in phosphorus-deprived Hyp mice and are in contrast to the decrease we (30) and others (36) observed in normal mice and rats. The 24-hydroxylase is capable of the complete catabolism of 1,25(OH)2D and its 25OHD precursor via a five-step reaction process that includes 24-hydroxylation, 24-oxidation, 23-hydroxylation, side-chain cleavage, and subsequent production of the final degradative products, calcitroic acid, and cholacalcioic acid (37, 38, 39). Thus, the decrease in the serum concentration of 1,25(OH)2D in phosphorus-restricted Hyp mice (23) can be attributed to an increase in its renal catabolism as well as to a reduction in its renal synthesis, the latter attributable to the reduction in renal P450c1{alpha} mRNA abundance and 1{alpha}-hydroxylase activity documented in the present study.

The question remains as to the underlying mechanisms for the disordered regulation of both the P450c1{alpha} and P450c24 genes by phosphorus in Hyp mice. Using nuclear run-on assays, we showed that phosphorus restriction increases transcription of the P450c1{alpha} gene in wild-type mice (30) and of the P450c24 gene in Hyp mice (35). These observations and those of the present study suggest that loss of Phex function in Hyp mice gives rise to disordered transcriptional regulation of both the P450c1{alpha} and P450c24 genes. The extent to which posttranscriptional or posttranslational mechanisms contribute to regulation of expression of these genes remains to be determined. Our finding that diet-induced values of renal P450c1{alpha} mRNA abundance vary directly and significantly with those of 1{alpha}-hydroxylase activity in both wild-type and Hyp mice suggest that posttranslational mechanisms contribute little to the disordered regulation of renal 1,25(OH)2D production by phosphorus in the mutant strain.

The Phex protein exhibits significant homology to the M13 family of zinc metallopeptidases, which activate (40, 41) or inactivate (42) a variety of biologically active peptides. Based on these findings, it was postulated that Phex is involved in the processing of a peptide factor(s) that regulates skeletal mineralization, renal phosphate transport, and vitamin D metabolism. Although the nature of this factor is unknown, recent studies of two renal phosphate wasting disorders that are associated with disturbed regulation of vitamin D metabolism, autosomal dominant hypophosphatemic rickets (ADHR) (43, 44, 45) and oncogenic hypophosphatemic osteomalacia (OHO) (also known as tumor-induced osteomalacia) (1, 46, 47), provide information that may be relevant to the pathophysiology of Hyp/XLH.

ADHR and OHO share clinical and biochemical features with XLH, including hypophosphatemia, inappropriately low or normal serum concentrations of 1,25(OH)2D, and rickets or osteomalacia (1). ADHR is caused by mutations in the FGF23 gene, which encodes a novel secreted peptide that is processed to amino- and carboxy-terminal peptides. All ADHR patients harbor mutations in the peptide’s furin cleavage site that prevent the processing of mutant FGF-23 (48), presumably resulting in its accumulation in the plasma. In addition, FGF-23 is abundantly expressed in tumors that cause OHO (49, 50), a disorder that completely resolves upon surgical removal of the tumor. Because extracts from these tumors inhibit phosphate transport in renal proximal tubule cells in vitro (51, 52), it has been suggested that FGF-23 is responsible for this inhibition. In support of this hypothesis are the findings that recombinant FGF-23 inhibits phosphate transport in renal proximal tubule cells in vitro (53), and that administration of recombinant FGF-23 to mice induces hypophosphatemia and increased renal phosphate clearance (50). It is of interest that FGF-23-treated mice also exhibit decreased serum concentrations of 1,25(OH)2D (50, 54, 55) due to reduced renal 1{alpha}-hydroxylase mRNA expression (50, 55) and increased 24-hydroxylase mRNA expression (55). Taken together, these findings suggest that a common circulating factor, perhaps FGF-23, plays a central pathogenetic role in ADHR, OHO, and XLH. Consistent with this hypothesis is the recent finding that serum concentrations of FGF-23 are increased in patients with OHO and XLH (56). However, the mechanisms by which FGF-23, or other peptide factors, regulates renal phosphate handling, 1{alpha}-hydroxylase expression, and bone mineralization, will require further study.

In summary, we report that the regulation of both the P450c1{alpha} and P45024 genes by phosphorus is disordered in Hyp mice, at the level of renal 1{alpha}-hydroxylase activity and P450c1{alpha} and P450c24 mRNA abundance. In wild-type mice, renal 1{alpha}-hydroxylase activity and P450c1{alpha} mRNA expression are inversely related to serum phosphorus concentration, whereas in Hyp mice these renal parameters are directly related to serum phosphorus concentration. Despite these differences, P450c1{alpha} and P450c24 gene expression are reciprocally related in both mouse strains. The mechanism whereby loss of Phex function contributes to the abnormalities in vitamin D metabolism in Hyp mice requires further study.


   Footnotes
 
This work was supported by grants from the NIH (DK-54433, to A.A.P.), the Canadian Institutes of Health Research (FRN 14107, to H.S.T.), and gifts from the David Carmel Trust (to A.A.P.).

Abbreviations: ADHR, Autosomal dominant hypophosphatemic rickets; Hyp, X-linked hypophosphatemic; 1,25(OH)2D, 1,25-dihydroxyvitamin D; OHO, oncogenic hypophosphatemic osteomalacia; XLH, X-linked hypophosphatemia.

Received February 25, 2003.

Accepted for publication April 16, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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