Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enzyme replacement-therapy for a severely affected premature boy (birthweight: 2,380 g, GA: 36 weeks) with hypophosphatasia was attempted by infusions of purified human hepatic alkaline phosphatase. Treatment (1.2 IU/kg/min) started at age three weeks and was repeated in weekly intervals until age 10 weeks, when the child died. Samples of alkaline phosphatase were diluted with 10 ml of physiological saline and infused over 30 min via an umbilical arterial catheter. No toxic or allergic side effects were observed. Serum alkaline phosphatase activity increased from 3 IU/L before treatment to a maximum level of 195 IU/L with a half-life time between 37 and 62 hours. Urinary excretion of phosphoethanolamine decreased during therapy from a maximal level of 9.5 to 5.5 mumol/mg creatinine (normal: less than 0.4 mumol/mg creatinine). Calcium, phosphorus, parathormone and 1,25-diOH vitamin D levels were within normal range. Sequential radiographic studies showed no improvement of bone mineralization. Bone morphology was studied by light and electron microscopy before treatment and post mortem. The borderline between mineralized and unmineralized matrix was more distinct after treatment and on the electron microscopical level initial spots of mineralization were more frequent between the collagen fibrils compared to the biopsy specimen before treatment. In contrast to previous studies however, only woven and bundle bone structures were studied from the tibial crest, where the lack of osteoblast-like cells upon the newly formed osteoid matrix was prominent.
 ...
PMID:Biochemical and morphological effects of human hepatic alkaline phosphatase in a neonate with hypophosphatasia. 264 53

The classic oral features of hypophosphatasia, namely, premature tooth loss and large pulp spaces, were found in a young adult woman with bone and joint pains. A study of 22 family members revealed several with dental abnormalities such as abnormal enamel, dentin, or cementum formation, decreased mandibular bone density, and abnormally large pulp spaces. Only the propositus' sister fulfilled the biochemical criteria for hypophosphatasia. Biochemical examination of an extracted tooth from this sister showed phosphate and alkaline phosphatase values that were 7 to 10 times lower than normal and reduced concentrations of the essential cofactors Zn++ and Co++. The spectrum of dental abnormalities is reviewed. This family study reveals that enamel hypoplasia, increased pulp spaces, and premature tooth loss are present not only in the deciduous but also in the permanent dentition. These findings should draw the dentist's attention to this condition.
 ...
PMID:Dental aspects of hypophosphatasia: a case report, family study, and literature review. 265 97

Hypophosphatasia is a heritable disorder characterized by defective bone mineralization and a deficiency of liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity in serum and tissues. Severe forms of the disease, which are generally lethal in infancy, are inherited in an autosomal recessive fashion. The gene defects that produce hypophosphatasia are poorly understood, but many are likely to occur at the L/B/K ALP locus. To investigate these gene defects, we analyzed L/B/K ALP DNA, RNA, and enzyme activity in cultured dermal fibroblasts from 14 patients with perinatal or infantile hypophosphatasia and from 12 normal individuals. Southern blot analyses of the L/B/K ALP genes from patients and controls revealed identical restriction patterns. Control fibroblast ALP activity correlated with the corresponding L/B/K ALP mRNA levels estimated by blot hybridization analysis and densitometry (r = .94, P less than .0001). In contrast, fibroblasts from the hypophosphatasia patients were deficient in ALP enzyme activity but expressed apparently full-sized L/B/K ALP mRNA at normal levels. Bone specimens from one of the patients were examined and found to be deficient in histochemical ALP but contained immunologic cross-reactive material detected by anti-human liver ALP antiserum. Our results demonstrate that the deficiency of ALP activity in fibroblasts from 14 patients with severe hypophosphatasia is not due to decreased steady-state levels of the corresponding mRNA. The presence of enzymatically inactive L/B/K ALP protein in one of these patients is consistent with a point mutation or small in-frame deletion in the coding region of L/B/K ALP gene.
 ...
PMID:Analysis of liver/bone/kidney alkaline phosphatase mRNA, DNA, and enzymatic activity in cultured skin fibroblasts from 14 unrelated patients with severe hypophosphatasia. 270 56

Hypophosphatasia is an inherited disease in which a deficiency of the bone/liver/kidney or tissue nonspecific isoenzyme of alkaline phosphatase (AP; EC 3.1.3.1) occurs. All forms of the disease are characterized clinically by defective mineralization. Several biochemical abnormalities are associated with the deficiency of AP activity, e.g., increased urinary excretion of inorganic pyrophosphate (PPi) and phosphoethanolamine (PEA). Measurement of these analytes in kindreds of patients with hypophosphatasia may be useful in identifying carriers, and in understanding the inheritance of the disease. We studied biochemically 22 members of the kindred of a 24-year-old woman with hypophosphatasia. We measured activity of AP in serum and leukocytes, and the urinary excretion of PPi and PEA. Within this kindred, urinary excretion of PPi appeared to indicate carrier status, and among the clinically normal adults, values for this analyte were inversely correlated with the activity of AP in serum. These results suggest that urinary excretion of PPi is sensitive to subtle changes in the activity of AP.
 ...
PMID:Hypophosphatasia: biochemical screening of a Dutch kindred and evidence that urinary excretion of inorganic pyrophosphate is a marker for the disease. 284 9

Prenatal diagnosis of hypophosphatasia was made by alkaline phosphatase (ALP) assay on a chorionic villus sample taken in the first trimester. Monoclonal antibodies against the liver/bone/kidney (LBK) and placental isoenzymes of ALP were used, and the bound isoenzymes were quantified by an amplification system. Very low activities of the LBK isoenzyme indicated an affected fetus. Diagnosis was confirmed by ultrasound scan at 15 weeks' gestation, and by ALP measurement in amniotic fluid supernatant and fetal serum.
 ...
PMID:First trimester diagnosis of hypophosphatasia with a monoclonal antibody to the liver/bone/kidney isoenzyme of alkaline phosphatase. 286 77

The serum concentration of parathormone is usually normal in hypophosphatasia, a rare disease with a defect of bone mineralisation and low serum alkaline phosphatase activity. Nevertheless there are three cases in the literature presenting a hyperparathyroidism with or without hypercalcemia. No anomaly of parathyroid was found at autopsy. The authors describe the first cases of hypophosphatasia with low serum concentration of parathormone and raise the possibility of a trouble in the calcium-parathormone feed-back. They also emphasize the interest of the urinary pyrophosphate excretion. Its increase seem to be the most constant and the most specific biological disorder.
 ...
PMID:[Inorganic pyrophosphates and parathormone in hypophosphatasia. Study of a family]. 300 10

Inorganic pyrophosphate (PPi) influences the formation of bone mineral. In the rare inherited disease hypophosphatasia, abnormal extracellular metabolism of PPi occurs together with defective skeletal mineralization. The primary biochemical defect in this condition is a deficiency of the bone/liver/kidney (tissue nonspecific) isoenzyme of alkaline phosphatase (AP), an enzyme that catalyzes the extracellular breakdown of PPi. Fibroblast lines derived from patients with hypophosphatasia manifest the deficiency of AP activity that occurs in vivo and thus are a suitable model for this condition. Using these cells from patients with the severe (infantile) form of the disease, we examined aspects of PPi metabolism in hypophosphatasia, in particular the formation of PPi from ATP by ecto-nucleoside triphosphate (NTP) pyrophosphatase. This enzyme is believed to catalyze the extracellular generation of PPi in vivo. We found that normal fibroblasts possess ecto-NTP pyrophosphatase and that infantile hypophosphatasia cell lines have normal activity and cellular distribution of this enzyme compared with cell lines derived from age-matched normal subjects. This suggests that extracellular generation of PPi is normal in hypophosphatasia. The results also provide further evidence that ecto-NTP pyrophosphatase and AP are distinct entities and that hypophosphatasia does not involve a general loss of enzyme activities from cell surfaces.
 ...
PMID:Normal activity of nucleoside triphosphate pyrophosphatase in alkaline phosphatase-deficient fibroblasts from patients with infantile hypophosphatasia. 302 80

To explore the hypothesis that alkaline phosphatase (ALP) functions in the regulation of cell growth and differentiation, we examined in tissue culture several parameters of cell proliferation demonstrated by dermal fibroblasts from patients with infantile hypophosphatasia--a heritable form of rickets/osteomalacia which is characterized biochemically by marked deficiency of activity of the "tissue nonspecific" (bone/liver/kidney) ALP isoenzyme. Methylumbelliferyl phosphate was used as the fluorogenic substrate to assay ALP activity in cell homogenates from patients and age-, sex-, and passage-matched control cells. The nature of the enzymatic defect in the patient fibroblasts involved their failure to increase the specific activity of ALP during growth to confluency. Patient cell monolayers contained, on average, about 2-3% of control ALP activity (several lines consistently demonstrated less than 1%). Nevertheless, patient cells grew normally both in early and late passage, and in either serum-containing or defined medium. Contact inhibition appeared to be intact in the patient fibroblasts, since the protein and DNA content of their culture dishes were similar to controls just as the cells became visually confluent, and when examined 1 week after they reached monolayer. Light and phase-contrast microscopy revealed no abnormalities in the appearance of patient cells during growth or at confluency. The mean volume of proliferating patient cells was also normal. Despite profound deficiency of constitutive ALP activity, dermal fibroblasts from infants with hypophosphatasia exhibit normal growth parameters in cell culture.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Infantile hypophosphatasia fibroblasts proliferate normally in culture: evidence against a role for alkaline phosphatase (tissue nonspecific isoenzyme) in the regulation of cell growth and differentiation. 310 94

Evidence that infantile hypophosphatasia may result from defective regulation of an intact structural gene for the tissue nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (TNSALP) was explored by studying physicochemical properties of ALP in sonicates of monolayers of cultured dermal fibroblasts from 7 patients (PT) and 5 age- and sex-matched control (CT) subjects. Both groups had low levels of ALP activity when assayed with 4-methylumbelliferyl phosphate substrate. The mean specific activity of ALP in the PT fibroblasts was markedly subnormal (Vmax less than 1% of CT), but apparently not from extracellular loss of enzyme, since defined medium had less ALP activity when conditioned by PT compared to CT cells. Although the mean Km for the sonicate ALP was similar for both groups at pH 10.1, pH optimum, thermal stability and response to several inhibitors appeared to be different. Nevertheless, it seemed that some TNSALP-like enzyme was present in the PT group. Exposure of cells in culture to 5-azacytidine and several putative inducers of ALP failed to increase the enzyme activity in either the PT or CT groups. Had the physicochemical properties of the constitutive (or inducible) ALP been the same in the PT and CT cell groups, the findings would have provided evidence for the generality of our previous observations in one patient which indicated that defective regulation of an intact structural gene for TNSALP could account for hypophosphatasia.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Infantile hypophosphatasia: enzymatic defect explored with alkaline phosphatase-deficient skin fibroblasts in culture. 310 77

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Clinical severity is variable, ranging from death in utero (due to severe rickets) to pathologic fractures first presenting in adult life. Affected siblings, however, are phenotypically similar. Severe forms of the disease are inherited in an autosomal recessive fashion; heterozygotes often show reduced serum ALP activity. The specific gene defects in hypophosphatasia are unknown but are thought to occur either at the L/B/K ALP locus or within another gene that regulates L/B/K ALP expression. We used the polymerase chain reaction to examine L/B/K ALP cDNA from a patient with a perinatal (lethal) form of the disease. We observed a guanine-to-adenine transition in nucleotide 711 of the cDNA that converts alanine-162 of the mature enzyme to threonine. The affected individual, whose parents are second cousins, is homozygous for the mutant allele. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolishes the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene results in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization.
 ...
PMID:A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. 317 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>