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:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Jejunal biopsies from 19 adult Greenland Eskimos were studied regarding disaccharidases, two intracellular beta-galactosidases, and morphological appearance. Fifteen of the patients (79%) had low lactase activity, and 3 of these (16%) had sucrase-isomaltase deficiency as well. Two patients had low trehalase activity. Microscopical appearance was essentially normal in all the biopsies, except for a certain stromal plasma cell infiltration. All the patients with low lactase activity had a measurable residual activity of brush border lactase, which was localized in the middle and apical parts of villi, as normally seen for digestive enzymes. Lysosomal acid beta-galactosidase and cytosol hetero beta-galactosidase were not altered. In the patients with sucrase-isomaltase deficiency there was a complete absence of active sucrase-isomaltase complex. The residual maltase, as well as the very weak residual isomaltase, was exerted exclusively by the heat stable maltases (maltase II and III). The material is the first one in which multiple, but not generalized disaccharidase deficiencies are demonstrated.
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PMID:Intestinal disaccharidases in Greenland Eskimos. 115 47

GM1-gangliosidosis is a genetic neurological disorder caused by mutations in the lysosomal acid beta-galactosidase gene. While its phenotypic expression is complex, it is usually classified as being of infantile, juvenile, or adult form, on the basis of age at onset, the rate of symptomatic progression, and severity of central nervous system involvement. We have analyzed the acid beta-galactosidase gene in 12 Japanese patients from nine families. The aim was to identify mutations in individual patients and then to examine possible correlation between the mutations and the clinical phenotypes. Northern blotting studies with a full-length human beta-galactosidase cDNA showed that the mRNA ranged from undetectable to substantially decreased in the infantile patients but was normal in quantity and size in all juvenile and adult patients. Four distinct missense mutations have been identified, each limited to the respective clinical forms within our small-size samples. In the infantile patient with decreased but detectable mRNA, a point mutation was found resulting in Arg49----Cys. In the infantile patient with nearly undetectable mRNA, mutation Arg457----Ter was identified. The mutation Arg201----Cys was found in all four of the juvenile patients, while all six adult patients were homozygous for the point mutation Ile51----Thr. The mutations found in the juvenile and adult patients alter restriction sites in the normal gene and thus are amendable to quick screening. The prediction that these mutations are responsible for the clinical disease was confirmed by no expression of the catalytic activity of the mutant proteins in the COS-I cell expression system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients. 190 89

A full-length cDNA coding for mouse lysosomal acid beta-galactosidase has been isolated on the basis of homology with the human gene. Catalytic activity toward 4-methylumbelliferyl beta-D-galactoside in the COS-1 cell expression system provided positive proof for its authenticity. The sequence analysis showed that the degree of similarity between the human and mouse enzymes was approximately 70% in the nucleotide sequence and nearly 80% in the amino acid sequence. The deduced primary amino acid sequences of the enzymes from the two species indicated that, of the seven possible N-glycosylation sites in the human enzyme, five are conserved in the mouse enzyme. Three additional possible N-glycosylation sites, not present in the human enzyme, are found in the primary amino acid sequence of the mouse enzyme. All seven cysteine residues in the mouse enzyme are conserved in the human enzyme. Although the nucleotide sequence could be aligned to 60% identity with the E. coli beta-galactosidase, similarity in the amino acid sequence was minimal.
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PMID:Molecular cloning of mouse acid beta-galactosidase cDNA: sequence, expression of catalytic activity and comparison with the human enzyme. 212 9

1. Acid beta-galactosidase [EC 3.2.1.23] of porcine adrenocortical lysosomes, assayed for its activity towards p-nitrophenyl-beta-D-galactopyranoside, showed two activity peaks on gel filtration profile at pH 7.4, one corresponding to a molecular weight of approximately 270,000 (termed form A3) and the other about 65,000 (termed form A1). 2. Another form of acid beta-galactosidase with a molecular weight of about 130,000 (termed form A2) was found when the high speed extract or partially purified form A1 was chromatographed on Sephadex G-150 at pH 4.5. 3. In the presence of 0.1 M NaCl or saturating amounts of substrate at pH 4.5, the high speed extract showed the aggregation of form A2 yielding form A3. Dissociation of form A3 back to form A1 was observed on incubation at 37 degrees C in 0.02 M sodium phosphate buffer, pH 7.4, and that was followed by irreversible enzyme inactivation. 4. Dissociation of form A3 into form A1 and enzyme inactivation in phosphate buffer, pH 7.4, were prevented by addition of 0.1 M NaCl. 5. The interconvertible enzymic forms showed the same pH-activity profiles and Michaelis constants. 6. These results suggest that the lysosomal acid beta-galactosidase in the porcine adrenal cortex exists in vivo as the dimer, and that the dimer may further aggregate into the tetramer.
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PMID:Reversible aggregation and stability of lysosomal acid beta-galactosidase from porcine adrenal cortex. 678 33

With the goal of improving the detection of lysosomal sphingolipid hydrolases within intact cells, we have recently synthesized a new fluorophor, O-[4-(1-imidazolyl)butyl]-2,3-dicyano-1,4-hydroquinonyl beta-D-galactopyranoside (Im-DCH-beta-Gal). In the present study, we evaluated the interaction of Im-DCH-beta-Gal and its tetraacetate derivative, Im-DCH-beta-Gal(OAc)4, with living human fibroblasts. Im-DCH-beta-Gal was shown to be a specific substrate for human lysosomal beta-galactosidase in cell homogenates. Im-DCH-beta-Gal(OAc)4 was taken up and hydrolyzed by normal fibroblasts under physiological culture conditions. Very little hydrolysis of Im-DCH-beta-Gal(OAc)4 was observed in fibroblasts genetically deficient in lysosomal acid beta-galactosidase or in normal cells pretreated with the lysosomal inhibitors chloroquine and ammonium chloride. Analysis of substrate processing by cells indicated that normal and acid beta-galactosidase-deficient cells showed similar rates of uptake and deacetylation of Im-DCH-beta-Gal(OAc)4, with an 80% decrease in the rate of deglycosylation of substrate by beta-galactosidase-deficient fibroblasts. However, under our conditions, the fluorescent product was not well retained by cells. Our results indicate that this novel class of compounds may be useful in measuring lysosomal enzyme function in intact cells and may have application as a fluorescent marker for genetically altered cells.
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PMID:Hydrolysis of a novel lysosomotropic enzyme substrate for beta-galactosidase within intact cells. 798 68

GM1-gangliosidosis is a progressive neurological disease in humans caused by deficiency of lysosomal acid beta-galactosidase, which hydrolyses the terminal beta-galactosidic residue from ganglioside GM1 and other glycoconjugates. In this study, we generated a mouse model for GM1-gangliosidosis by gene targeting in embryonic stem cells. The mouse homozygous for the disrupted beta-galactosidase gene showed beta-galactosidase deficiency, presented with progressive spastic diplegia, and died of emaciation at 7-10 months of age. Pathologically, PAS-positive intracytoplasmic storage was observed in neuronal cells of various areas in the brain. Biochemical analysis revealed a marked accumulation of ganglioside GM1 and asialo GM1 in brain tissue. This animal model will be useful for pathogenetic analysis and therapeutic trial of human GM1-gangliosidosis.
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PMID:Beta-galactosidase-deficient mouse as an animal model for GM1-gangliosidosis. 933 86

Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two different disorders: GM1 gangliosidosis, which involves the nervous system and visceral organs to varying extents, and Morquio's syndrome type B (Morquio B disease), which is a skeletal-connective tissue disease without any CNS symptoms. This article shows that transduction of human GM1 gangliosidosis fibroblasts with retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to complete correction of the enzymatic deficiency. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. Cross-correction experiments using retrovirus-modified cells as enzyme donors showed, however, that the human enzyme is transferred at low efficiencies. Experiments using a different retrovirus vector carrying the human cDNA confirmed this observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high levels of enzymatic activity. Furthermore, the mouse enzyme was found to be transferred to human cells at high efficiency. Enzyme activity measurements in medium conditioned by genetically modified cells suggest that the human beta-galactosidase enzyme is less efficiently released to the extracellular space than its mouse counterpart. This study suggests that lysosomal enzymes, contrary to the generalized perception in the field of gene therapy, may differ significantly in their properties and provides insights for design of future gene therapy interventions in acid beta-galactosidase deficiency.
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PMID:Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme. 1075 51

A six-month-old shiba dog with a one-month history of progressive motor dysfunction showed clinical signs of a cerebellar disorder, including ataxia, dysmetria and intention tremor of the head. Histopathological and ultrastructural studies revealed distended neurons packed with membranous cytoplasmic bodies throughout the central nervous system. The activities of lysosomal acid beta-galactosidase in its leucocytes and liver were less than 2 per cent of the control levels, and the compound accumulated in the brain was identified as GM1 ganglioside. A sibling which died immediately after birth was shown to have a beta-galactosidase deficiency in the brain and visceral organs. A family study revealed that the sire and dam of the probands were heterozygotes with approximately half of the normal level of beta-galactosidase activity, suggesting an autosomal recessive pattern of inheritance.
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PMID:GM1 gangliosidosis in shiba dogs. 1088 96

A deficiency of lysosomal acid beta-galactosidase leads to G(M1)-gangliosidosis in humans, which progressively and profoundly affects the brain and other organs mainly in the early infantile period. We report the pathology of mice with targeted disruption of the beta-galactosidase gene. In the central nervous system, vacuolated neurons appeared in the spinal cord 3 days after birth. The vacuolation extended to neurons in the brainstem, cerebral cortex, hippocampus and thalamus and ballooning neurons became prominent with age. The vacuolation also appeared in Purkinje cells without a marked ballooning change. Reactive astrogliosis in the entire brain was marked at the terminal stage of the disease. Immunohistochemical study using anti-ganglioside G(M1) and G(A1) antibodies revealed extensive accumulation of G(M1) and G(A1) in the cerebral neurons. In the liver, however, accumulation of G(M1) was localized in the cytoplasm of hepatocytes, whereas that of G(A1) was localized in foamy macrophages and Kupffer cells. There were no significant abnormalities in the bone, bone marrow, or cornea at any stage. Although there are some phenotypic and biochemical differences between this knockout mouse and human GM1 gangliosidosis, the mouse will be a useful model for therapeutic trials for the human disease.
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PMID:Development of lysosomal storage in mice with targeted disruption of the beta-galactosidase gene: a model of human G(M1)-gangliosidosis. 1157 47

The specific identification of cellular senescence in clinical material has important implications for determining the role of senescence in age-related pathologies and in neoplasia in certain tumours. One suggested marker of senescence is the histochemical identification of a specific beta-galactosidase enzyme operative at pH 6.0. However, recent data indicate that this enzyme may not be specific for senescence in all tissues and probably represents the expression of endogenous lysosomal acid beta-galactosidase, which is expressed by a variety of differentiated cell types.
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PMID:Markers of senescence? 1192 Jul 34


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