Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Abstract

Phenotypic heterogeneity in X-linked hypophosphatemic rickets (XLH) is ascribed to variable penetrance of the genetic abnormality. However (4.7±0.3 mg/dl) and phosphate (P)-depleted mice (4.9±0.4) was significantly less than normal (8.4±0.5). Consistent with P depletion, the Gy mice exhibited enhanced renal 25(OH)Dla-hydroxylase activity (9.3±0.6 fmol/mg kidney per min), similar to that of P-depleted normals (9.1±1.5), but significantly greater than that of controls (3.1±0.3). Such normal enzyme responsiveness was confirmed upon PTH stimulation (1 IU/h s.c.), which revealed that Gy mice increased renal 1-hydroxylase (59±7.7) similarly to normals (65±7.7) and Pdepleted animals (58.4±7.8). Calcitonin administration also enhanced enzyme function comparably in the animal models. Evidence confirming normally responsive calcitriol production in untreated Gy mice included increased serum 1,25-dihydroxyvitamin D levels, gastrointestinal calcium absorption, and urinary calcium. The normally regulated vitamin D metabolism in Gy mice indicates that biochemically diverse disease may result from mutations in the gene family regulating renal P transport and underlying X-linked hypophosphatemia. We suspect such heterogeneity is due to altered P transport at variable segments of the proximal convoluted tubule. (J. Clin. Invest. 1990. 85:334-339.) calcitriol -hypophosphatemia.

A New Kindred with Hereditary Hypophosphatemic Rickets with Hypercalciuria: Implications for Correct Diagnosis and Treatment

“…It is of inter est to note that recently, a similar pattern has been observed in 2 murine homologues of the human diseases, the hypophosphatemic (Hyp) and gyrorotary (Gy) mice [17][18][19]. It has been documented that in the Gy-mouse, vitamin D metabolism is normally regulated [19], contrary to the Hypmouse [17], Thus, the Gy-mouse may become an experimen tal model for the human disease HHRH, while the more familiar Hyp-mouse is a valid model of XLH. However, in the murine models, the two mutations are located at distinc tively different sites along the X chromosome, while in the human disorders, the XLH mutation is localized at the X chromosome [1]; the HHRH mutation, in all kindreds de scribed, is autosomal [3][4][5]8].…”

“…In XLH, there seems to be an abnormality in the phosphate (and PTH) regulation of the renal 25(OH)D-1-a-hydroxylase, with an inappropriately low l,25(OH)2D serum level in relation to the degree of phosphatemia, while in HHRH, this regulatory axis seems to be normal with subsequently elevated serum concentrations of l,25(OH)2D. It is of inter est to note that recently, a similar pattern has been observed in 2 murine homologues of the human diseases, the hypophosphatemic (Hyp) and gyrorotary (Gy) mice [17][18][19]. It has been documented that in the Gy-mouse, vitamin D metabolism is normally regulated [19], contrary to the Hypmouse [17], Thus, the Gy-mouse may become an experimen tal model for the human disease HHRH, while the more familiar Hyp-mouse is a valid model of XLH.…”

Evidence for Abnormal Translational Regulation of Renal 25-Hydroxyvitamin D-1α-Hydroxylase Activity in theHyp-Mouse

“…We assayed maximum velocity of renal 25(OH)D-1␣-hydroxylase activity in kidney homogenates by a modification of our previously described methods (1,16 10,000 cpm, in 20 l ethanol, to measure recovery during subsequent purification steps, the reaction mixtures were transferred to 125-ml separatory funnels and 6 ml buffer and 6.5 ml chloroform added. The lipid phase was transferred to glass vials and dried under a stream of nitrogen.…”

Femoral abnormalities and vitamin D metabolism in X‐linked hypophosphatemic (Hyp and Gy) mice

“…The urinary level of calcium was measured by atomic absorption spectrophotometry. The phosphate Normal female (n= 8) Hyp male (n = 4) Hyp female (n = 10)…”