Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present report outlines an attempt to characterize inorganic phosphate uptake by human jejunal mucosa using biopsy material obtained from six patients affected by the X-linked form of vitamin D-resistant rickets and six control subjects. The tissue from control subjects accumulated 32P actively in a linear fashion against time. The incorporation of inorganic phosphate into organophosphate derivatives is rapid and equilibrates after 10 min at an inorganic over total phosphate ratio of 0.45. Concentrative uptake and incorporation were both suppressed by anaerobiosis or cyanide. Rates of phosphate uptake and incorporation into the organic derivatives by the tissue of hypophosphatemic patients are comparable with normal values. Saturation kinetics observed over a wide range of substrate concentrations (0.003 to 3 mM) elicits only one transport system with an apparent Michaelis constant of 0.2 mM and a maximum velocity of 0.7 mmol/liter/40 min. The kinetic data obtained from the patients do not strikingly differ from the control values. The chemical analysis of the phosphate content of intestinal mucosa from two patients and two control subjects indicates that the tissue is not specifically phosphate-depleted in the mutant individuals. These results are in accordance with the positive results obtained with the oral replacement therapy in familial hypophosphatemia.
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PMID:Intestinal phosphate transport in familial hypophosphatemic rickets. 18 Apr 85

Use of 1,25(OH)2D3 (calcitriol) can be of benefit in the treatment of two hereditary types of rickets and osteomalacia, vitamin D dependency type I (VDD1) and X-linked hypophosphatemic vitamin D-resistant rickets (HPDR). VDD1 is due to inadequate activation of 25(OH)D to 1,25(OH)2D, leading to very low circulating levels of 1,25(OH)2D in plasma; the basic abnormality appears to be an alteration in renal 1 alpha-hydroxylase activity. In VDD1, replacement therapy with calcitriol results in complete correction of the abnormal phenotype. By contrast, in HPDR, plasma levels of 25(OH)D and 1,25(OH)2D are in the normal range, although it has been demonstrated that the ability of patients to produce 1,25(OH)2D under conditions of stress is impaired. When started early in life, the use of phosphate salts in HPDR generally results in healing of rickets, normal growth, and correction of lower limb deformities. However, osteomalacia is not corrected by treatment with phosphate, either alone or in combination with vitamin D. By pharmacologically increasing the level of 1,25(OH)2D3 in these patients, there is often a dramatic improvement in the appearance of the trabecular surface, leading to correction of the osteomalacic component of HPDR; in addition, the secondary hyperparathyroidism observed in previous patients treated with phosphate and vitamin D is easier to control. Closed medical follow-up allows the prevention of renal damage that could result from long-term administration of calcitriol.
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PMID:Calcitriol treatment in vitamin D-dependent and vitamin D-resistant rickets. 215 42

Over the past decade our understanding of the pathogenesis of altered mineral homeostasis in chronic renal failure (CRF) and X-linked hypophosphatemic vitamin D-resistant rickets (XLH) has increased, and has provided a rational approach for the use of the 1 alpha-hydroxylated analogues of vitamin D in their therapy. Recent evidence suggests that intracellular phosphate (Pi) retention in CRF plays a major role in decreasing serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, which are responsible for the progressive rise in serum parathyroid hormone (PTH) concentrations through the direct action of 1,25(OH)2D on the parathyroid gland. 1,25(OH)2D levels affect the number of intracellular 1,25(OH)2D receptors, preproPTH mRNA levels and the set point for calcium suppression of PTH release. Further in experimental CRF, the maintenance of normal 1,25(OH)2D levels prevents parathyroid gland hyperplasia. These studies indicate that depressed renal 1 alpha-hydroxylase activity due to Pi retention is a major factor in directly increasing PTH secretion, which in turn contributes significantly to the severity of renal osteodystrophy. Thus the aim of therapy in early CRF should be to maintain normal levels of 1,25(OH)2D which can be achieved by either dietary Pi restriction and oral Pi binders or by administering small doses of 1 alpha-hydroxylated metabolites. The long term consequences of these two different therapeutic regimens still need to be assessed. In XLH, evidence is rapidly accumulating that alterations in 1 alpha-hydroxylase activity secondary to impaired Pi handling by the proximal renal tubule, results in decreased serum 1,25(OH)2D levels, which might be responsible for a number of the associated abnormalities documented in both treated and untreated XLH patients. These abnormalities include decreased calcium and Pi absorption by the intestine and low normal serum calcium values. In vitamin D- and Pi-treated patients 1,25(OH)2D levels are further depressed, with a resultant increase in PTH values, and the development of tertiary hyperparathyroidism in a small number of patients. The use of 1 alpha-hydroxylated analogues rather than vitamin D together with Pi supplements decreases the severity of hyperparathyroidism, improves Pi absorption from the intestine and markedly ameliorates the degree of osteomalacia. Whether long-term therapy with these analogues will prevent the development of tertiary hyperparathyroidism in patients with XLH is unclear.
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PMID:Recent advances in pediatric metabolic bone disease: the consequences of altered phosphate homeostasis in renal insufficiency and hypophosphatemic vitamin D-resistant rickets. 216 13

X-linked hypophosphatemic (Hyp) mice are a model of human sex-linked vitamin D-resistant rickets. Young adult Hyp mice are characterized by osteomalacia and decreased bone mineral content. However, older heterozygous Hyp female mice increase in bone mineral content with age so that by one year of age the bone mass/mm femoral length equals or exceeds normal females. To test for the occurrence of this mineral accretion in Hyp male mice and in homozygous Hyp female mice, femora from all 3 Hyp genotypes as well as normal male and female mice were analyzed at various ages from one to 52 weeks of age. Compared to normal mice, all three Hyp genotypes were depressed in bone ash, femoral length, and ash/length ratio at 13 weeks of age. After that age the femora of both heterozygous and homozygous Hyp females showed a slow mineral accretion and, by 52 weeks of age, a normal ash/length ratio. However, the femora of Hyp males, as well as those of normal males, failed to increase in bone mineral content or ash/length ratio after 13 weeks of age. The differences between male and female Hyp mice could not be explained by differences in the plasma levels of calcium, phosphate, or alkaline phosphatase. Increased bone mineral content in older Hyp mice was seen in both heterozygous and homozygous females but not in hemizygous males. Thus, the basis for this increase is not incomplete dominance of the Hyp gene in females nor the Lyon hypothesis. The accretion of mineral in older female Hyp mice despite lifelong reduced plasma phosphate levels suggests that there are factors other than phosphate that also regulate mineral accretion in this bone disease.
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PMID:Mineral uptake by the femora of older female X-linked hypophosphatemic (HYP) mice but not older male HYP mice. 304 Mar 11

X-linked hypophosphatemic (Hyp) mice are a model for human X-linked (familial) hypophosphatemia (vitamin D-resistant rickets). In several studies, Hyp mice have been shown to exhibit either normal intestinal phosphate absorption or malabsorption of phosphate. These apparently conflicting reports led us to further investigate intestinal phosphate absorption. Isolated intestinal segments in vivo were used in C57BL/6J normal and Hyp mice, both male and female. 33P was placed in the segment in 2 mM Na2HPO4 + 150 mM NaCl, pH 7.2. Mice at 4, 7, and 12 weeks of age were used. No significant differences in phosphate absorption were found between the sexes. At 4 weeks of age, Hyp mice showed significant malabsorption of phosphate, with the jejunum being the most severely affected. Malabsorption was judged by significantly more 33P remaining in the lumen, less in the intestinal tissue, and less in the plasma. At 7 weeks of age, these same trends were seen but at a nonsignificant level. By the 12th week of life, the absorption of 33P was similar in Hyp and normal mice. Thus, phosphate malabsorption in Hyp mice is an age-related phenomena. These changes parallel the malabsorption of calcium in young Hyp mice and reflect the lowered plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) levels of young Hyp mice.
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PMID:Malabsorption of phosphate by the intestines of young X-linked hypophosphatemic mice. 314 95

X-linked hypophosphatemic (Hyp) mice are a model for human sex-linked vitamin D-resistant rickets. We have reported intestinal malabsorption of calcium in young Hyp mice, and in this report we have explored the mechanism for it. To test for resistance of the intestine to 1,25(OH)2 vitamin D3, this hormone was continually infused via osmotic minipumps into 4-week-old normal and Hyp mice at 0, 17, 50 or 150 ng/kg/day. After 3 days, 45Ca and inorganic 32P were administered by gavage, and the mice were sacrificed on the fifth day. The Hyp mice showed responses to the hormone equivalent to the normal mice in terms of increased intestinal absorption of both 45Ca and 32P, increased plasma isotope levels, increased femoral isotope content, and increased duodenal and renal 9 kD vitamin D-dependent calcium-binding protein (calbindin-D9K; CaBP). Plasma 1,25(OH)2D was measured in these mice. There were significant correlations of plasma 1,25(OH)2D to the intestinal absorption of 45Ca and 32P and to duodenal and renal CaBP. Plasma 1,25(OH)2D was also measured in stock normal and Hyp mice and was found to be lower in 4-week-old Hyp mice than in 4-week-old normal mice (113 +/- 10 pM (n = 18) vs. 67 +/- 10 (n = 20), normal vs. Hyp, p less than .01), but unchanged at 13 weeks of age (77 +/- 13 (n = 13) vs. 70 +/- 15 (n = 15), NS). This observed difference in plasma 1,25(OH)2D between normal and Hyp mice at 4 weeks of age was sufficient to explain the observed normal-to-Hyp differences in intestinal absorption of 45Ca and duodenal and renal CaBP. It also explained 72 +/- 18% of the observed difference in 32P absorption. We conclude that Hyp mouse intestine is not resistant to 1,25(OH)2D and that the lower plasma 1,25(OH)2D of 4-week-old Hyp mice causes intestinal malabsorption of calcium and phosphate.
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PMID:Evidence that low plasma 1,25-dihydroxyvitamin D causes intestinal malabsorption of calcium and phosphate in juvenile X-linked hypophosphatemic mice. 345 58

Hyp mice are a model for X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. Previous reports indicate alterations in the nervous system of these mice. The present study examined rearing and step climbing behavior in Hyp mice in the staircase test. We found that male Hyp mice have large reductions in both the number of rears and steps climbed when compared to normal male mice. When compared to normal female mice, female Hyp mice have a small reduction in the number of steps climbed but no significant reduction in the number of rears. However, they have greater rearing and climbing activity than male Hyp mice. These reductions in activity are not correlated with the severity of bone disease. Gonadectomy had no effect on activity in male mice but reduced activity comparably in both Hyp and normal female mice. We conclude that Hyp mice have altered behavior in the staircase test and that the magnitude and type of the alteration is influenced by the sex of the animal.
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PMID:Rearing and step climbing behavior of X-linked hypophosphatemic (Hyp) mice. 361 50

The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur (35S) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hyp mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia.
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PMID:Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse. 386 38

Hyp mice are a model for human X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. It has previously been observed that Hyp mice have a greater food consumption per gram body weight than do normal mice. This led to the search for some alteration in metabolism in Hyp mice. We found that oxygen consumption was significantly higher in Hyp mice than in normal C57BL/6J mice and this was accompanied by an increased percentage of cardiac output being delivered to organs of heat production (liver and skeletal muscle), to the skin, and to bone and a decreased percentage to the gastrointestinal tract of Hyp mice. The increased oxygen consumption in Hyp mice was not associated with increased plasma free T4 levels and was not affected by alterations in plasma phosphate produced by a low phosphate diet. The cause of the increased oxygen consumption is not known, and the role that this change and reported changes in distribution of cardiac output may play in the development of X-linked hypophosphatemia is also unknown. Study of the cardiovascular and thermoregulatory systems in Hyp mice should help increase understanding of the underlying mechanisms of this disease.
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PMID:Increased metabolic rate in X-linked hypophosphatemic mice. 394 Aug 55

Craniosynostosis and associated craniofacial deformities, such as frontal bossing, often occur as symptoms of vitamin D-resistant rickets in children. Similar skull deformities develop in mice with X-linked dominant hypophosphatemia, the most common form of vitamin D-resistant rickets. These mice have a short, wide, high neurocranium, which suggested an inhibition of coronal suture growth. To study this question, we compared histologically the postnatal development of the coronal sutures in normal and hypophosphatemic mice between 1 and 13 weeks of age. Premature fusion of the coronal suture occurred in hypophosphatemic mice by 4 weeks of age. The proportion of the suture obliterated by bone varied among individual animals, but craniosynostosis was present in all animals studied at 4 weeks and older. Fusion of the coronal suture did not occur through 13 weeks of age in any of the normal mice studied. The x-linked hypophosphatemic mouse is an animal model that can be used to study the role of vitamin D-resistant rickets in the development of craniosynostosis, to relate craniosynostosis to the development of associated skull deformities, and to test new treatment procedures.
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PMID:Craniosynostosis in vitamin D-resistant rickets. A mouse model. 626 7


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