Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Clinical, morphological and biochemical data, including data obtained from the application of subcellular fractionation techniques to liver biopsy specimens, are presented for two patients with the Dubin-Johnson-Sprinz (DJS) syndrome. 2. Subcellular fractionation experiments demonstrate that the lysosomes, which have strikingly reduced equilibrium densities, accumulate melanin. Morphological studies confirm the presence of pigments within lysosomes. 3. Although there are increased activities of lysosomal acid hydrolases in the liver tissue from patients with the DJS syndrome, the integrity of these organelles is essentially normal and therefore the accumulation of pigment would not be expected to initiate liver damage. The DJS syndrome is thus a benign type of secondary lysosomal storage disease.
Clin Sci Mol Med 1977 Mar
PMID:Lysosomal changes in liver tissue from patients with the Dubin-Johnson-Sprinz syndrome. 1 5

The transport of 3H-fucose- and 3H-glucosamine-labelled glycoproteins in the absorptive cells of cultured human small-intestinal tissue was investigated with light- and electron-microscopical autoradiography. The findings showed that these glycoproteins were completed in the Golgi apparatus and transported in small vesicular structures to the apical cytoplasm of these cells. Since this material arrived in the cell coat on the microvilli and in the lysosome-like bodies simultaneously, a crinophagic function of these organelles in the regulation of the transport or secretion of cell-coat material was supported. In the absorptive cells of patients with fucosidosis or Hunter's type of lysosomal storage disease, a smiliar transport of cell-coat material to the lysosome-like bodies and a congenital defect of a lysosomal hydrolase normally involved in the degradation of cell-coat material, can explain the accumulation of this material in the dense bodies.
Virchows Arch B Cell Pathol Incl Mol Pathol 1979 Jun 29
PMID:Transport of radiolabelled glycoprotein to cell surface and lysosome-like bodies of absorptive cells in clutured small-intestinal tissue from normal subjects and patients with a lysosomal storage disease. 4 6

Deficient arylsulfatase-A activity is diagnostic of a neurodegenerative human lysosomal storage disease, metachromatic leukodystrophy. Paradoxically, similar enzyme deficiency also occurs in normal individuals, who are known as being pseudo arylsulfatase-A deficient. We showed previously that this phenotype is associated with a structural gene mutation that produces an exceptionally labile enzyme. We now report on the nature and consequence of this mutation. When the mutant arylsulfatase-A is deglycosylated by endoglycosidase H, only one smaller molecular species was generated, instead of the two from the normal enzyme. This is consistent with the loss of one of the two N-linked oligosaccharide side chains known to be present on the wild-type enzyme. Quantitative analysis of mannose and leucine incorporation showed that the mutant enzyme incorporated two- to tenfold less mannose than the normal enzyme on a molar basis. This deficient glycosylation was specific to arylsulfatase-A. Another lysosomal enzyme not affected in this mutation, beta-hexosaminidase, was glycosylated normally in the mutant cells. The remaining single oligosaccharide side chain released from the mutant arylsulfatase-A by pronase digestion was normally processed to complex and high-mannose forms. However, the high-mannose side chains contained 30% fewer phosphorylated residues than those of the normal enzyme. Nevertheless, this reduced level of phosphorylation did not prevent targeting of the mutant enzyme to the lysosomes, a process normally mediated through phosphorylated mannose residues. In conclusion, pseudo arylsulfatase-A deficiency is a unique human mutation associated with reduced glycosylation and phosphorylation of a lysosomal enzyme with the loss of one of the two carbohydrate side chains. The mutation results in greatly reduced enzyme stability, thus indicating a role for oligosaccharides in maintaining enzyme stability within the degradative environment of the lysosomes. However, the residual catalytic activity or subcellular targeting of the mutant enzyme was not affected. These properties probably account for the benign clinical presentation of pseudo arylsulfatase-A deficiency.
Mol Cell Biochem 1990 Feb 09
PMID:Deficient glycosylation of arylsulfatase A in pseudo arylsulfatase-A deficiency. 196 15

Human lysosomal beta-glucosidase (D-glucosyl-acylsphingosine glucohydrolase, EC 3.2.1.45) is a membrane-associated enzyme that cleaves the beta-glucosidic linkage of glucosylceramide (glucocerebroside), its natural substrate, as well as synthetic beta-glucosides. Experiments with cultured cells suggest that in vivo this glycoprotein requires interaction with negatively charged lipids and a small acidic protein, SAP-2, for optimal glucosylceramide hydrolytic rates. In vitro, detergents (Triton X-100 or bile acids) or negatively charged ganglioside or phospholipids and one of several "activator proteins" increase hydrolytic rate of lipid and water-soluble substrates. Using such in vitro assay systems and active site-directed covalent inhibitors, kinetic and structural properties of the active site have been elucidated. The defective activity of this enzyme leads to the variants of Gaucher disease, the most prevalent lysosomal storage disease. The nonneuronopathic (type 1) and neuronopathic (types 2 and 3) variants of this inherited (autosomal recessive) disease but panethnic, but type 1 is most prevalent in the Ashkenazi Jewish population. Several missense mutations, identified in the structural gene for lysosomal beta-glucosidase from Gaucher disease patients, are presumably casual to the specifically altered posttranslational oligosaccharide processing or stability of the enzyme as well as the altered in vitro kinetic properties of the residual enzyme from patient tissues.
Crit Rev Biochem Mol Biol 1990
PMID:Acid beta-glucosidase: enzymology and molecular biology of Gaucher disease. 212 41

Interspecific somatic cell hybrids were analyzed by genetic complementation to determine if a lysosomal storage disease in sheep associated with deficiencies of beta-galactosidase and alpha-neuraminidase was homologous with any of four beta-galactosidase-deficient human diseases. Fibroblasts from beta-galactosidase-deficient sheep, cats, and human patients were fused and assayed histochemically for beta-galactosidase, with 5-bromo-4-chloro-3-indolyl beta-D-galactoside. We observed complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from patients with galactosialidosis or mucolipidosis type II, but no complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from human or feline GM1 gangliosidosis (type I) or from human mucopolysaccharidosis type IVB fibroblasts. We conclude that the ovine disease is due to a mutation at the genetic locus homologous with that of GM1 gangliosidosis and mucopolysaccharidosis type IVB, suggesting that the primary defect in the ovine disease is a mutation of the beta-galactosidase structural gene.
Somat Cell Mol Genet 1989 Nov
PMID:Interspecific genetic complementation analysis of human and sheep fibroblasts with beta-galactosidase deficiency. 251 53

Suramin-induced lysosomal storage disease reproduced in the rat was extended to the mouse with the attempt to characterize enzymatically and morphologically heterogeneous responses of various organs to the drug. Suramin administration strikingly decreased (3-6 days afterward) the activity of beta-glucuronidase in all tissues studied (kidney, liver, heart, and skeletal muscle). The enzymatic responses were small in the activities of beta-N-acetyl-glucosaminidase. The activity of arylsulfatase A decreased to a varying degree in mouse tissues, but in rats the activity increased in liver and skeletal muscle. The activity of cathepsin D increased in rat tissues. Suramin induced morphological changes characteristic to lysosomal storage diseases in kidney and liver but not in heart and skeletal muscle of both mice and rats. Kidney was appreciably more susceptible to suramin than liver. The occurrence of lysosomal accumulations, membranous lamellar inclusions, and granular material were most prominent in tubular cells of kidney and in Kupffer cells of liver. These cells also presented intensive Alcian blue staining. Interestingly, the enzymatic and morphological responses did not correlate with each other, which may reflect differences in the regulation of lysosomal functions in various cell types.
Exp Mol Pathol 1986 Aug
PMID:Morphological and enzymatic heterogeneity of suramin-induced lysosomal storage disease in some tissues of mice and rats. 287 99

In Gaucher disease the genetic lack of acid beta-glucosidase activity causes glucocerebroside to accumulate in the lysosomes of macrophage-derived cells, producing large characteristic Gaucher cells. The formation of Gaucher cells seems to be central to the pathobiology of this lysosomal storage disease. To develop a model simulating this process, cultured murine peritoneal macrophages were treated with conduritol B epoxide, a specific irreversible inhibitor of acid beta-glucosidase, for 6, 15, and 24 days. The conduritol B epoxide-treated macrophages accumulated glucocerebroside as a function of time, progressing to a fivefold elevation over control values after 24 days of treatment. Electron microscopy of the cells treated for 24 days reveals characteristics of Gaucher cells, including striations consisting of oriented fibrils. With conventional staining techniques, these fibrils have an appearance considered highly characteristic of Gaucher disease. Thus, macrophages treated with conduritol B epoxide are a useful model for studying the metabolic consequences and morphologic features associated with glucocerebroside accumulation in Gaucher cells.
Exp Mol Pathol 1988 Jun
PMID:Macrophages exposed in vitro to conduritol B epoxide resemble Gaucher cells. 337 56

Mucopolysaccharidosis type VII is a lysosomal storage disease resulting from a deficiency of beta-glucuronidase (BG) activity. To facilitate the investigation of mutation in the disease and provide molecular diagnostic tools for affected families, we have isolated human BG cDNA clones. The SV40-transformed human fibroblast cDNA library of Okayama and Berg [Mol. Cell. Biol. 3 (1982) 280-289] was screened with a fragment of a murine BG cDNA clone (pGUS-1). The 17 human cDNA clones (pHUG) isolated were identical by restriction mapping, varying only in length. The pHUG clones show 80% DNA sequence homology with pGUS-1 in a 198-bp PvuII-SstI restriction fragment. Both pGUS-1 and the pHUG clones contained an open reading frame (ORF) throughout the sequenced region with a predicted amino acid sequence homology of 73%. Expression in Escherichia coli of a 1150-bp fragment of pHUG-1 subcloned in pUC9 resulted in an isopropyl-thio-beta-galactoside (IPTG)-inducible 35-kDal fusion protein which was specifically immunoprecipitated by goat anti-human BG immunoglobulin G (IgG). This evidence provides direct confirmation that the pHUG cDNA clones correspond to human BG.
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PMID:Isolation and expression in Escherichia coli of a cDNA clone encoding human beta-glucuronidase. 392 35

Infantile acid maltase deficiency (Pompe's disease, glycogenosis II) is a progressive, severe lysosomal storage disease in which skeletal and cardiac muscle fibers accumulate membrane-bound and free glycogen and are destroyed. New information in this report concerns 1) early hypertrophy of skeletal muscle fibers, 2) absence of size change as glycogen is lost, and 3) the ultrastructure of end-stage fibers empty of glycogen. Muscle fibers enlarge as they accumulate glycogen and then stay large as glycogen is lost. They are so large that, if empty fibers did in fact contain glycogen, over 80% of the muscle would be glycogen instead of 6.3-11.5% (from 37 published determinations). Fibers that have reached "empty" end-stage are shown to be more numerous than all other stages combined in biopsies from infantile acid maltase deficiency. Ultrastructurally, end-stage fibers contain much "empty" space (liquid-filled without fine structure) and various remnants and masses of altered myofibrillar and sarcoplasmic material. Many broken membranes originally enclosing glycogen in storage lysosomes are seen. A single broken membrane can enclose an area larger than the cross section area of a muscle fiber from a normal infant. The results support the proposal of Hers that the disease is due to a deficiency of the single lysosomal enzyme acid maltase. The results also support the lysosomal rupture hypothesis of Griffin, which accounts for muscle fibers being more damaged than are other cells and for the release of glycogen to the sarcoplasm.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Infantile acid maltase deficiency. II. Muscle fiber hypertrophy and the ultrastructure of end-stage fibers. 619 86

We have identified a novel aspartylglucosaminuria (AGU) mutation in the second exon of the aspartylglucosaminidase (AGA) gene resulting in a lysosomal storage disease in a Puerto Rican pedigree. This T192-->A transversion causes replacement of Cys64 with a premature translational stop codon and the patients' fibroblasts exhibit dramatically decreased steady-state levels of AGA mRNA. Immunofluorescence analysis and analysis of immunoprecipitated metabolically labelled AGA polypeptides from patient fibroblasts unexpectedly revealed traces of normally sized inactive AGA precursor polypeptide instead of the predicted short polypeptide of 40 amino acids, thus demonstrating readthrough due to suppression of the premature translational stop codon. The translated AGA precursor is not processed further and remains inactive. The Cys64 substitution evidently disturbs the folding of the nascent polypeptide in the endoplasmic reticulum, thus preventing activation by proteolytic cleavage.
Hum Mol Genet 1994 Dec
PMID:Characterization of a point mutation in aspartylglucosaminidase gene: evidence for a readthrough of a translational stop codon. 788 26


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