Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the four existing isoforms of alkaline phosphatase (AP), the present study is devoted to tissue-nonspecific alkaline phosphatase (TNAP) in mineralized dental tissues. Northern blot analysis and measurements of phosphohydrolase activity on microdissected epithelium and ectomesenchyme, in situ hybridization, and immunolabeling on incisors confirmed that the AP active in rodent teeth is TNAP. Whereas the developmental pattern of TNAP mRNA and protein and the previously described activity were similar in supra-ameloblastic and mesenchymal cells, they differed in enamel-secreting cells, the ameloblasts. As previously shown for other proteins involved in calcium and phosphate handling in ameloblasts, a biphasic pattern of steady-state TNAP mRNA levels was associated with additional variations in ameloblast TNAP protein levels during the cyclic modulation process. Although the association of TNAP upregulation and the initial phase of biomineralization appeared to be a basic feature of all mineralized tissues, ameloblasts (and to a lesser extent, odontoblasts) showed a second selectively prominent upregulation of TNAP mRNA/protein/activity during terminal growth of large enamel crystals only, i.e., the maturation stage. This differential expression/activity for TNAP in teeth vs bone may explain the striking dental phenotype vs bone reported in hypophosphatasia, a hereditary disorder related to TNAP mutation. (J Histochem Cytochem 47:1541-1552, 1999)
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PMID:Differential expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) in rat odontogenic cells in vivo. 1056 38

McCune-Albright syndrome is a rare genetic disorder consisting of skin and bone dysplasia and peripheral endocrinopathies. Little data have been collected regarding bisphosphonate treatment of bone fibrous dysplasia in paediatric patients with this syndrome. The aim of our study was to investigate the therapeutic efficacy of pamidronate in these patients. Nine patients with moderate to severe forms of bone fibrous dysplasia were treated with pamidronate intravenously (0.5-1 mg/kg/daily for 2-3 d) at 0.5-1-y intervals. Patients were treated over a time period of 0.5-3.5 y. During treatment no spontaneous fracture occurred. Bone pain and gait abnormality due to pain disappeared after 2-3 therapeutic cycles. Cranial asymmetry and limb length discrepancy remained unchanged. Elevated serum alkaline phosphatase and urine hydroxyproline values were reduced by the treatment, demonstrating drug activity at the lesional level. The effectiveness of pamidronate was also seen at the non-lesional level through an increase in bone density. Radiographic and scintigraphic evidence of lesion healing was not attained. Pamidronate treatment can ameliorate the course of bone fibrous dysplasia in children and adolescents with McCune-Albright syndrome.
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PMID:Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome. 1070 89

Here we describe a method for the sensitive detection of a single-base mutation in DNA. We assembled a primer thiolated oligonucleotide, complementary to the target DNA as far as one base before the mutation site, on an electrode or a gold-quartz piezoelectric crystal. After hybridizing the target DNA, normal or mutant, with the sensing oligonucleotide, the resulting assembly is reacted with the biotinylated nucleotide, complementary to the mutation site, in the presence of polymerase. The labeled nucleotide is coupled only to the double-stranded assembly that includes the mutant site. Subsequent binding of avidin-alkaline phosphatase to the assembly, and the biocatalyzed precipitation of an insoluble product on the transducer, provides a means to confirm and amplify detection of the mutant. Faradaic impedance spectroscopy and microgravimetric quartz-crystal microbalance analyses were employed for electronic detection of single-base mutants. The lower limit of sensitivity for the detection of the mutant DNA is 1 x 10-14 mol/ml. We applied the method for the analysis of polymorphic blood samples that include the Tay-Sachs genetic disorder. The sensitivity of the method enables the quantitative analysis of the mutant with no PCR pre-amplification.
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PMID:Detection of single-base DNA mutations by enzyme-amplified electronic transduction. 1123 59

Pycnodysostosis is a rare hereditary bone abnormality with an autosomal recessive mode of inheritance. We report the clinical, radiologic, and endocrine status of 8 children with this rare disease. All patients had the characteristic phenotype of the disorder including short stature (8 of 8), increased bone density (7 of 8), separated cranial sutures (8 of 8), large fontanel with delayed closure (8 of 8), obtuse mandibular angle (8 of 8), delayed teeth eruption (8 of 8), enamel hypoplasia (7 of 8), dysplastic acromial ends of the clavicles (6 of 8), frontal bossing (6 of 8), ocular proptosis (8 of 8), and dysplastic nails (8 of 8). Developmental evaluation according to the revised Denever developmental screening showed normal motor, fine motor-adaptive language, and personal social abilities in all the children. All had normal hepatic and renal functions. Serum calcium and phosphorus concentrations were normal. Two children had low serum alkaline phosphatase concentration. Short stature is a characteristic feature of pycnodysostosis. Seven of the 8 children were born short (length standard deviation score [SDS] = -3 to -1.5). Deceleration of linear growth was significant during the first 3 years of life. All the children had height SDS below -3 at the end of their third year of life. Although short stature is a feature of this genetic disorder, defective growth hormone (GH) secretion in response to provocation with clonidine and glucagon was found in 4 of the 8 patients. These 4 patients had pituitary hypoplasia on the magnetic resonance imaging (MRI) of their brain. In addition, 3 of these 4 patients had demyelination of the cerebrum. Patients with pycnodysostosis (n = 8) had low circulating concentrations of insulin-like growth factor-1 (IGF-1) compared with normal age-matched short children with constitutional short stature (CSS). IGF-I increased significantly after injecting GH for 3 days in these patients. Physiologic replacement with GH (18 U/m(2)/week) divided in daily evening doses subcutaneously increased IGF-1 concentration and improved linear growth velocity and height standard deviation scores (HtSDS) in the 4 children with GH deficiency. These data ruled out GH resistance and proved the usefulness of GH therapy in the management of short stature in these patients. In summary, some patients with pycnodysostosis have partial GH deficiency and low IGF-1 concentration. GH therapy markedly increases IGF-I secretion and improves their linear growth. MRI study of the brain including the hypothalamic-pituitary area is recommended in these children because of the high incidence of pituitary hypoplasia and cerebral demyelination.
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PMID:Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. 1147 77

Thirteen patients with McCune-Albright syndrome (MAS) and bone fibrous dysplasia (BFD) have been treated for 2-6 years with pamidronate, an aminobisphosphonate which inhibits osteoclastic function. MAS is a rare genetic condition caused by constitutive activating mutations of the Gs protein and manifests with skin dysplasia, bone fibrous dysplasia, and multiple endocrinopathies. Raised serum alkaline phosphatase and urinary hydroxyproline have been reported in these patients, indicating bone metabolic hyperactivity. Encouraging therapeutic results have been achieved with pamidronate, mainly in adults. In our study, treatment reduced bone pain, fracture rate and metabolic indices of bone turnover, in particular significantly decreased bone alkaline phosphatase and cross-links (Wilcoxon test; p <0.06), and increased bone mineral density (DEXA). Signs of healing, such as thickening of the cortical bone, were found in some patients. Three patterns of MRI were found: homogeneous hypointense fibrous tissue, 'dotted' hypointense fibrous tissue, and hyperintense cystic images. Pamidronate treatment can be considered a favorable therapeutic option for patients with MAS.
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PMID:Pamidronate treatment in bone fibrous dysplasia in children and adolescents with McCune-Albright syndrome. 1219 52

Bone fibrous dysplasia is one of the main features of McCune-Albright syndrome, a rare genetic condition caused by constitutive activating mutations of Gs-protein and defined by skin dysplasia, bone fibrous dysplasia, and autonomous multiple endocrinopathies. Raised serum alkaline phosphatase (ALP) and urinary hydroxyproline levels indicating bone metabolic hyperactivity have been reported in these patients. Encouraging therapeutic results have been achieved, mainly in adults, with pamidronate, an aminobisphosphonate. In this study we investigate newer bone metabolic indices in a cohort of 11 children and adolescents treated with pamidronate. Tenfold increases of bone ALP and urinary pyridinoline cross-links were found and osteocalcin levels were twofold higher compared with reference values. After treatment, significant decreases in bone ALP and cross-links (Wilcoxon test P < 0.06) were found. Bone mineral density (BMD) significantly increased during treatment. There were signs of radiological healing as thickening of the cortical bone was found in some cases.
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PMID:Bone turnover in children and adolescents with McCune-Albright syndrome treated with pamidronate for bone fibrous dysplasia. 1220 Jun 45

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D(3)]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [(3)H]1,25-(OH)(2)D(3) in extracts from the patient's fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient's cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)(2)D(3) or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)(2)D(3)-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.
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PMID:A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. 1240 43

Hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). In this report, we present our findings on a young girl who exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25(OH)(2)D(3)]. The patient also had total body alopecia. Fibroblasts from the patient were cultured for analysis of the VDR structure and function. In [3H]1,25(OH)(2)D(3) binding assays, no significant specific binding to the VDR was observed in cytosols from the patient's fibroblasts. The patient's fibroblast were also totally resistant to high doses of 1,25(OH)(2)D(3) as demonstrated by their failure to induce expression of the 24-hydroxylase gene, a marker of 1,25(OH)(2)D(3) activity. DNA sequence analysis of the VDR gene uncovered a unique C to T mutation in exon 8. The mutation changed the codon for glutamine to a premature stop codon at amino acid 317 (Q317X). Restriction enzyme analysis showed that the patient was homozygous for the mutation. Both parents were heterozygous for the mutant allele. In conclusion, we have identified a novel mutation in the VDR, Q317X, as the molecular defect in a patient with HVDRR. The Q317X mutation deletes 110 amino acids of the ligand-binding domain of the VDR and results in the loss of [3H]1,25(OH)(2)D(3) binding and target gene transactivation.
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PMID:A novel nonsense mutation in the ligand binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. 1246 77

The amplified detection of a target DNA, based on the alkaline phosphatase oxidative hydrolysis of the soluble 5-bromo-4-chloro-3-indoyl phosphate to the insoluble indigo product as an amplification path, is addressed by two different sensing configurations. The accumulation of the insoluble product on Au electrodes or Au/quartz crystals alters the interfacial electron-transfer resistance at the Au electrode or the mass associated with the piezoelectric crystal, thus enabling the quantitative transduction of the DNA sensing by Faradaic impedance spectroscopy or microgravimetric quartz crystal microbalance measurements, respectively. One sensing configuration involves the association of a complex consisting of the target DNA and a biotinylated oligonucleotide to the functionalized transducers. The binding of the avidin/alkaline phosphatase conjugate to the sensing interface followed by the biocatalyzed precipitation provides the amplification path for the analysis of the target DNA. This analysis scheme was used to sense the target DNA with a sensitivity limit that corresponds to 5 x 10(-14) M. The second amplified detection scheme involves the use of a nucleic-acid-functionalized alkaline phosphatase as a biocatalytic conjugate for the precipitation of the insoluble product. Following this scheme, the functionalized transducers are interacted with the analyzed sample that was pretreated with the oligonucleotide-modified alkaline phosphatase, followed by the biocatalyzed precipitation as the amplification route for the analysis of the target DNA. By the use of this configuration, a detection limit corresponding to 5 x 10(-13) M was achieved. Real clinical samples of the Tay-Sachs genetic disorder were easily analyzed by the developed detection routes.
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PMID:Highly sensitive amplified electronic detection of DNA by biocatalyzed precipitation of an insoluble product onto electrodes. 1259 50

We have evaluated the potential of liver-directed, helper-dependent adenoviral (HDAd) vector-mediated gene therapy in the hemophilia B dog. Two dogs were injected intravenously with HDAd (3 x 10(12) VP/kg) bearing a liver-restricted canine coagulation factor IX (FIX) expression cassette. After injection, the whole blood clotting time for both dogs declined from >60 min to </=20 min for at least 604 and 446 days, respectively. Peak FIX activities of 34.1 and 129.2% were detected at 12x14 days and then slowly declined to 2 to 5% by 120 days and stabilized at these therapeutic levels for at least 418 and 257 days. For one dog, a peak FIX level of 500 ng/ml was achieved and stabilized at >170 ng/ml for at least 256 days. For the other dog, a peak FIX level of 1258 ng/ml was achieved and stabilized at >400 ng/ml for at least 213 days. Inhibitor formation was not evident in either animal. Importantly, whereas untreated hemophilia B dogs suffer five or six spontaneous bleeds per year, the treated dogs suffered no such bleeds postinjection. Significantly, this study is the first to demonstrate long-term phenotypic correction of a genetic disorder in a large animal with HDAd. Although no evidence of chronic toxicity was observed in either animal, systemic vector administration at 3 x 10(12) VP/kg was accompanied by acute, albeit transient and variable laboratory abnormalities (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatine phosphokinase, and platelet counts). The results of this study highlight both the potential benefit and the risk associated with systemic intravascular delivery of high-dose HDAd for liver-directed gene therapy.
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PMID:Sustained phenotypic correction of canine hemophilia B after systemic administration of helper-dependent adenoviral vector. 1600 63


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