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

---

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

A review is presented of the recent advances in: (i) clinical features, (ii) biochemistry and molecular biology of alkaline phosphatase, (iii) genetic defect in hypophosphatasia, and (iv) prenatal diagnosis. Despite the recent progress, the pathogenesis of hypophosphatasia is far from being elucidated. More clinical cases and further characterization of the alkaline phosphatase gene mutations are needed for better understanding of the clinical spectrum of the entity.
...
PMID:Genetic analysis of hypophosphatasia. 931 5

Hypophosphatasia was diagnosed in two boys aged four months and two years. This is a rare hereditary bone disease characterized by deficient activity of enzyme alkaline phosphatase. Increased levels of substrates of this enzyme are found: phosphoethanolamine in urine and pyridoxal phosphate in serum. Patients show defective bone mineralization, which results in severe deformities of limbs, thorax and skull and dental abnormalities (loss of teeth and caries). The disease is classified in four age-related forms: perinatal, infantile, childhood and adult hypophosphatasia. The perinatal form is usually lethal. There is no curative therapy. Recognition of the disease is of importance for genetic counselling.
...
PMID:[Childhood hypophosphatasia]. 938 Jan 89

Hypophosphatasia, a heritable disease characterized by deficient activity of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP), results in rickets and osteomalacia. Although identification of TNSALP gene defects in hypophosphatasia establishes a role of ALP in skeletal mineralization, the precise function remains unclear. The initial site of mineralization (primary mineralization) normally occurs within the lumen of TNSALP-rich matrix vesicles (MVs) of growth cartilage, bone, and dentin. We investigated whether defective calcification in hypophosphatasia is due to a paucity and/or a functional failure of MVs secondary to TNSALP deficiency. Nondecalcified autopsy bone and growth plate cartilage from five patients with perinatal (lethal) hypophosphatasia were studied by nondecalcified light and electron microscopy to assess MV numbers, size, shape, and ultrastructure and whether hypophosphatasia MVs contain apatite-like mineral, as would be the case if these MVs retained their ability to concentrate calcium and phosphate internally despite a paucity of TNSALP in their investing membranes. We found that hypophosphatasia MVs are present in approximately normal numbers and distribution and that they are capable of initiating internal mineralization. There is retarded extravesicular crystal propagation. Thus, in hypophosphatasia the failure of bones to calcify appears to involve a block of the vectorial spread of mineral from initial nuclei within MVs, outwards, into the matrix. We conclude that hypophosphatasia MVs can concentrate calcium and phosphate internally despite a deficiency of TNSALP activity.
...
PMID:Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals. 940 6

1. Hypophosphatasia is a disorder characterized by low serum levels of alkaline phosphatase (ALP) and a range of skeletal deformities. The levels of a number of phosphorylated metabolites, namely phosphoethanolamine and pyrophosphate, are characteristically raised. Levels of pyridoxal-5'-phosphate (PLP) have also been reported to be raised. 2. Hypophosphatasia is a rare disease and experience of measuring PLP in patients is lacking. We have had the chance to look at PLP levels in four families with hypophosphatasia, specifically to examine the quantitative relationship between ALP and PLP which has not been described before. 3. We confirmed that PLP levels are raised in hypophosphatasia and related to the disease severity. A significant negative linear relationship was found between the log PLP and log ALP (log PLP = 5.99-2.76 log ALP; r = -0.85, P < 0.001). 4. Measurement of PLP is simpler than some of the phosphorylated compounds, e.g. pyrophosphate. PLP may be a useful measure in patients with a suspected diagnosis of hypophosphatasia or for screening family members to detect potential heterozygotes and to monitor any response to therapy. 5. There did not appear to be any adverse clinical effects in relation to disturbed vitamin B6 metabolism in hypophosphatasia. 6. Vitamin B6 is used therapeutically in a number of conditions with monitoring of PLP levels. In these conditions PLP levels should be interpreted in conjunction with the prevailing serum ALP levels as the metabolism of these compounds is closely inter-related.
...
PMID:Relationship between serum alkaline phosphatase and pyridoxal-5'-phosphate levels in hypophosphatasia. 953 30

We have studied the biosynthesis and intracellular transport of tissue-nonspecific alkaline phosphatase (TNSALP) transiently expressed in COS-1 cells. Mutations were introduced into TNSALP to examine the effects of a single amino acid substitution on the activity and biosynthesis of TNSALP. The cells expressing wild-type TNSALP exhibited more than 200-fold higher alkaline phosphatase activity than untransfected ones. Pulse-chase experiments showed that TNSALP was synthesized as a 66-kDa endoglucosaminidase H (Endo H)-sensitive form and converted to EndoH-resistant forms with heterogenous molecular masses ( approximately 80 kDa), which finally appeared on the cell surface as judged by digestion with phosphatidylinositol-specific phospholipase C (PI-PLC). In contrast, a TNSALP with a Glu218-->Gly mutation exhibited no phosphatase activity at all and the 66-kDa Endo H-sensitive form was the only molecular species throughout the chase in the transfected cells. In accordance with this finding, digestion with PI-PLC and immunofluorescence observation confirmed that this mutant was never expressed on the cell surface. Another mutant with a Ala162-->Thr substitution, which naturally occurs in association with a lethal hypophosphatasia, exhibited a low activity and only a small fraction of the 66-kDa form acquired Endo-H resistance and reached the cell surface. Since the wild-type and the mutant TNSALPs were labeled with [3H]ethanolamine, a component of glycosylphosphatidylinositol (GPI), it is unlikely that the impaired intracellular transport of the two mutants is due to a failure in their modification by GPI. Interestingly, the 66-kDa Endo H-sensitive form of the TNSALP mutants but not that of the wild-type, was found to form an interchain disulfide-bonded high-molecular-mass aggregate within the cells. These results suggest that impaired intracellular transport of the TNSALP (Ala162-->Thr) molecule caused by its aggregation is the molecular basis for the lethal hypophosphatasia carrying this mutation.
...
PMID:Defective intracellular transport of tissue-nonspecific alkaline phosphatase with an Ala162-->Thr mutation associated with lethal hypophosphatasia. 956 33

Hypophosphatasia is a rare disorder characterised by low levels of serum alkaline phosphatase activity resulting in abnormal phosphorylated metabolites and varying skeletal abnormality. We have followed a patient with adult type hypophosphatasia for over ten years who has also shown a persistently elevated tartrate resistant acid phosphatase activity (TRAP) without any obvious cause. Characterisation of this TRAP by polyacrylamide gel electrophoresis (pH 4.0) showed migration to band 5 position. Molecular weight determination by FPLC and an estimate of the molecular weight by gradient gel electrophoresis gave a molecular weight of 29,000-43,600. This molecular weight makes it unlikely for this to be a IgG/TRAP complex persisting in the circulation. Paranitrophenylphosphate was the preferred substrate. This characterises the enzyme as type 5 acid phosphatase which is of the mononuclear/phagocyte type, possibility of osteoclastic origin, though the tissue source remains unknown.
...
PMID:Persistently raised serum acid phosphatase activity in a patient with hypophosphatasia: electrophoretic and molecular weight characterisation as type 5. 956 36

One point mutation which converts glycine-317 to aspartate of tissue-nonspecific alkaline phosphatase (TNSALP) was reported to be associated with lethal hypophosphatasia (Greenberg, C. R., et al. Genomics 17, 215-217, 1993). In order to define the molecular defect of TNSALP underlying the pathogenesis of hypophosphatasia, we have examined the biosynthesis of TNSALP with a Gly317-->Asp substitution. When expressed in COS-1 cells, the mutant did not exhibit alkaline phosphatase activity at all, indicating that the replacement of glycine-317 with aspartate abolishes the catalytic activity of TNSALP. Pulse-chase experiments showed that the newly synthesized mutant failed to acquire Endo H-resistance and to reach the cell surface. Interestingly, this TNSALP mutant was found to form a disulfide-bonded high-molecular-mass aggregate and was rapidly degraded within the cell, though the mutant protein was modified by glycosylphosphatidylinositol (GPI). Lactacystin, an inhibitor of the proteasome, obstructed the degradation of the mutant protein, suggesting the involvement of proteasome as a part of quality control of TNSALP.
...
PMID:Intracellular retention and degradation of tissue-nonspecific alkaline phosphatase with a Gly317-->Asp substitution associated with lethal hypophosphatasia. 961 60

Tissue nonspecific alkaline phosphatase (AP) plays a well-known role in bone mineralization. This role was first suggested by a human AP deficiency disease, hypophosphatasia. Further studies with AP gene knockout mice have also suggested a role for AP in mineralization. However, AP is also expressed in other human tissues besides bone and cartilage, and this raises a question as to whether AP may also play a role in pathological mineralization such as dystrophic and vascular calcification. In vitro studies carried out in our laboratory indicate that a variety of cell types stably expressing membrane-bound AP can affect extracellular mineralization regardless of the tissue from which the cell lines originated (e.g. fibroblasts, vascular endothelial cells, or renal epithelial cells). This AP-mediated extracellular mineralization is both substrate/dependent and culture environment/dependent and may be consistent with a putative role for AP in pathological mineralization in tissues other than bone and cartilage. In this regard, it is interesting to note that high levels of AP are observed in vascular endothelia of small arterioles in brain and heart. It is probable that expression of AP in small arterioles of brain and heart may also contribute to the vascular hardening and calcification observed in humans. This in turn could be related to vascular aging, vascular disease, and the resultant weakening of and/or rupture of vessel walls.
...
PMID:New face of an old enzyme: alkaline phosphatase may contribute to human tissue aging by inducing tissue hardening and calcification. 970 Mar 94

Hypophosphatasia is a rare heritable inborn error of metabolism characterized by abnormal bone mineralization associated with a deficiency of alkaline phosphatase. The clinical expression of hypophosphatasia is highly variable, ranging from death in utero to pathologic fractures first presenting in adulthood. We investigated the tissue-nonspecific alkaline phosphatase (TNSALP) gene from a Japanese female patient with hypophosphatasia. By a quantitative polymerase chain reaction (PCR) method, the amount of TNSALP mRNA appeared to be almost equal to that in normal individuals. Gene analysis clarified that the hypophosphatasia originated from a missense mutation and a nucleotide deletion. The missense mutation, a C--> T transition at position 1041 of cDNA, results in an amino acid change from Leu to Phe at codon 272, which has not yet been reported. The previously reported deletion of T at 1735 causes a frame shift mutation downstream from Leu at codon 503. Family analysis showed that the mutation 1041T and the deletion 1735T had been inherited from the proband's father and mother, respectively. An expression experiment revealed that the mutation 1041T halved the expression of alkaline phosphatase activity. Using homology analysis, the Leu-272 was confirmed to be highly conserved in other mammals.
...
PMID:A novel missense mutation of the tissue-nonspecific alkaline phosphatase gene detected in a patient with hypophosphatasia. 974 27

Lethal hypophosphatasia, spur type: case report and fetopathological study: Hypophosphatasia (HP) is characterised by severe undermineralisation of the skeleton owing to deficiency of tissue nonspecific alkaline phosphatase. Clinically a perinatal, infantile, childhood and adult type is distinguished. Clinical signs in the perinatal type of HP show considerable overlap with other skeletal dysplasias such as osteogenesis imperfecta type IIA and type IIC, and achondrogenesis type IA. If present, "spurs" of the limbs are diagnostic for HP. We present a prenatally diagnosed case of HP and discuss the differential diagnosis based on clinical, radiological and pathological findings. Our findings indicate that two types of spurs can be distinguished in hypophosphatasia: midshaft type and joint type.
...
PMID:Lethal hypophosphatasia, spur type: case report and fetopathological study. 977 43


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

---