Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0205700 (ash)
 15,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new dominant mutation in the laboratory mouse, hypophosphatemia (gene symbol Hyp), has been identified. The Hyp gene is located on the X-chromosome and maps at the distal end. Mutant mice are characterized by hypophosphatemia, bone changes resembling rickets, diminished bone ash, dwarfism, and high fractional excretion of phosphate anion (low net tubular reabsorption). Phosphate supplementation of the diet from wearning prevents the appearance of severe skeletal abnormalities. The hypophosphatemic male mouse resembles human males with X-linked hypophosphatemia and the Hyp gene is presemably homologous with the X-linked human gene. The mouse model should facilitate study of the defect in transport of plasma inorganic phosphate anion.
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PMID:Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. 18 49

Since the deficiency of ornithine carbamoyltransferase (OCT) is inherited as an X-linked dominant trait in sparse-fur with abnormal skin and hair (Spf-ash) mice, the livers of heterozygous Spf-ash females show mosaicism in regard to OCT. We induced enzyme-altered foci and nodules, presumptive preneoplastic lesions for hepatocellular carcinomas, in the livers of OCT mosaic mice (Spf-ash x C3H F1), and investigated the clonality of the lesions. Simultaneous histochemical staining for OCT and gamma-glutamyl transpeptidase (GGT) demonstrated that all GGT-positive lesions (ranging in size from 3 cells to a few millimeters in diameter) were either positive or negative for OCT, and no mosaic lesions were detectable. The results indicate that individual enzyme-altered hepatocytic lesions are the result of clonal proliferation.
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PMID:Clonal origin of gamma-glutamyl transpeptidase-positive hepatic lesions induced by initiation-promotion in ornithine carbamoyltransferase mosaic mice. 289 63

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

The sparse fur with abnormal skin and hair (Spf-ash) mouse is a model for the human X-linked hereditary disorder, ornithine transcarbamylase (OTC) deficiency. In Spf-ash mice, both OTC mRNA and enzyme activity are 5% of control values resulting in hyperammonemia, pronounced orotic aciduria and an abnormal phenotype characterized by growth retardation and sparse fur. Using microinjection, we introduced a construction containing rat OTC cDNA linked to the SV40 early promoter into fertilized eggs of Spf-ash mice. The expression of the transgene resulted in the development of a transgenic mouse whose phenotype and orotic acid excretion are fully normalized. Thus, the possibility of correcting hereditary enzymatic defect by gene transfer of heterologous cDNA coding for the normal enzyme has been demonstrated.
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PMID:Correction of mouse ornithine transcarbamylase deficiency by gene transfer into the germ line. 316 66

Enzymatic assay, electrophoretic immunoblotting and RNA dot-blot techniques were employed to investigate the expression of the ornithine transcarbamylase (OTC) gene in liver and small intestine of Sparse fur mice with abnormal skin and hair (Spf-ash) and Sparse fur mice (Spf) which exhibit an X-linked OTC deficiency. We found a reduced OTC activity in these two tissues. We now show that this reduction is less pronounced in the intestine than in the liver of the Spf-ash strain. During the first 2 weeks of life, the deficiency appears to be less severe than in the adult mice. The enzymatic activity of carbamylphosphate synthetase I (CPS), another enzyme of the urea cycle, is significantly modified in the Spf mutant strain only.
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PMID:Compared expression levels of ornithine transcarbamylase and carbamylphosphate synthetase in liver and small intestine of normal and mutant mice. 316 57

We have reported that X-linked hypophosphatemic (Hyp) and normal mice respond equally to the administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] with uptake of 45Ca from an oral test meal as judged by the isotope remaining in the fecal samples. To determine whether this was due to specific stimulation of calcium absorption, as opposed to changes in calcium secretion or transit time, 1,25(OH)2D3 was administered to 4-week-old (young) and 13-week-old (adult) normal and Hyp mice at a dose of 0.12 micrograms/kg per day by continual infusion from an Alzet minipump. After 3 days of infusion, absorption of 45Ca from the isolated duodenum was measured in situ. Malabsorption of calcium was shown in vehicle-treated 4-week-old Hyp mice by significantly more 45Ca remaining in the intestinal segment and by significantly reduced plasma levels and reduced skeletal levels of 45Ca. Treatment of the young mice, both normal and Hyp, with 1,25(OH)2D3 resulted in increased absorption of 45Ca, increased plasma 45Ca, and increased incorporation of 45Ca into the femur. The young Hyp mice treated with 1,25(OH)2D3 showed a significant increase in femoral ash weight. At 13 weeks of age both normal and Hyp vehicle-treated mice showed equivalent absorption of calcium, and both responded to 1,25(OH)2D3 administration with enhanced calcium absorption. At both ages plasma phosphate rose in only the Hyp mice treated with 1,25(OH)2D3, whereas plasma and urine calcium were increased in only the hormone-treated normal mice. In conclusion, 1,25(OH)2D3 stimulates the absorption of calcium in the isolated duodenum of the young Hyp mouse with equal potency to that of young normal mice.
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PMID:Increased intestinal absorption of calcium in young and adult X-linked hypophosphatemic mice after the administration of 1,25-dihydroxyvitamin D3. 321 10

Femoral and skeletal mineralization were studied in normal and X-linked hypophosphatemic (Hyp) mice from birth to 13 weeks of age. Although the Hyp mice were continuously hypophosphatemic, their body weight, trunk length, femoral ash weight and total body calcium content were not significantly affected through 3 weeks of age. Tail length and femoral length were depressed by less than 10%. Between 3 and 7 weeks of age the normal mice continued their rapid growth, but there was little further lengthening of the femur or tail in the Hyp mice; body weight and trunk length fell behind the normals; and there was no further accumulation of femoral ash weight or total body calcium and little increase in total body phosphate. After 7 weeks of age the Hyp mice resumed accumulation of femoral and total body mineral.
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PMID:Changing patterns of femoral and skeletal mineralization during growth in juvenile X-linked hypophosphatemic mice. 406 87

Besides rickets and osteomalacia, the X-linked hypophosphatemic male mouse (Hyp/Y) presents with low serum calcium (Ca) and increased urinary hydroxyproline (OH-Pro) excretion, suggesting a parathyroid hormone (PTH)-stimulated bone resorption despite reduced magnesium (Mg) bone content. In this study, we have investigated by histochemical methods the state of bone resorption in 50-day-old untreated Hyp/Y mice and the effects of 4 wk of Mg therapy or dietary lactose supplementation on bone formation and resorption. Mineral and skeletal changes were evaluated on serum, urinary and bone ash concentrations of Ca, phosphorus (P) and Mg, and by histomorphometric analysis of tetracycline double labeled undeclalcified caudal vertebrae. The number of acid phosphatase stained chondroclasts and osteoclasts was lower than normal in untreated Hyp/Y and was restored after Mg therapy while the osteoclastic surface was increased above normal. Accordingly, serum P and urinary Ca, P, Mg, cAMP and OH-Pro were increased while TmP/GFR was unchanged. On the other hand, dietary lactose corrected serum Ca which probably suppressed PTH secretion since the renal P conservation was improved and the osteoclast number and the osteoclastic surface were decreased. Both treatments reduced the growthplate and osteoid seam thickness and increased the bone calcification rate. The results indicate that the low skeletal Mg present in Hyp/Y partially impairs bone responsiveness to PTH since Mg therapy restored the osteoclastic bone resorption which secondarily provided new minerals for bone mineralization. The greater than normal bone resorption found in Mg treated-Hyp/Y and the decreased bone resorption observed in lactose treated animals indicate that the chronic hypocalcemia induces secondary hyperparathyroidism in Hyp/Y mice.
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PMID:Effects of magnesium and lactose supplementation on bone metabolism in the X-linked hypophosphatemic mouse. 682 87

The X-linked hypophosphatemic (Hyp) mouse presents with biochemical and skeletal abnormalities similar to those of human vitamin D-resistant rickets and hence is considered as a model of the human disease. In an attempt to correct osteomalacia, young (21-day-old) mutant male mice were infused continuously for 4 weeks with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3; 0.05--0.25 microgram/kg . day]. Mineral and skeletal changes were assessed by serum, urinary, and bone ash concentrations of calcium, phosphorus, and magnesium and by histomorphometric analysis of bone formation measured on histological sections of tetracycline dual labeled undecalcified caudal vertebrae. Treatment with 1,25-(OH)2D3 produced a dose-dependent elevation of serum phosphorous that could be assigned to increased intestinal phosphate absorption. Concomitantly, epiphyseal, endosteal, and periosteal bone mineralization were improved in correlation with both the dosage of 1,25-(OH)2D3 and the serum phosphorus level. Normalization of serum calcium and phosphorus but not of urinary phosphate excretion were achieved together with complete healing of bone mineralization when the highest doses of 1,25-(OH)2D3 (0.175--0.35 microgram/kg . day) were given. The data show that rickets and osteomalacia, which characterize the young Hyp mouse, can be healed by 1,25-(OH)2D3 in doses high enough to normalize serum mineral concentrations. Unlike the renal phosphate leak, the phenotypic expression of the Hyp gene pertaining to bone mineralization is then corrected by 1,25-(OH)2D3 supplementation.
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PMID:Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse. 689 84

A study of skeletal development in X-linked hypophosphatemic (Hyp) mice revealed that radiographic characteristics of the disease appear as early as seven days after birth and that an unexpected transitory metaphyseal radio-opacity occurs in the long bones of the Hyp mice. Hyperostotic osteomalacia appears at the first week, peaks at the third week, and starts to fade by the fourth week. Undecalcified bone sections of three-week-old mice revealed an increased amount of trabecular bone in the metaphysis of the Hyp mice accounting for the increased radio-opacity. Blood chemistry data in three-week-old mice showed a low plasma phosphate, a slight hypocalcemia and elevated alkaline phosphatase. Three-week-old Hyp mice had a reduced percentage of magnesium in their bone ash compared to normal. The blood chemistry data resembled those of adult Hyp mice and did not explain the increased metaphyseal bone mass. The mechanism underlying this genetic abnormality of bone is unclear.
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PMID:Increased metaphyseal bone mass in the young X-linked hypophosphatemic (Hyp) mouse. 733 40


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