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)

The interaction of the sulfatide activator protein with different glycosphingolipids have been studied in detail. The following findings were made. 1. The sulfatide activator protein forms water-soluble complexes with sulfatides [Fischer, G. and Jatzkewitz, H. (1977) Hoppe-Seyler's Z. Physiol. Chem. 356, 6588-6591] and various other glycospingolipids. 2. In the absence of degrading enzymes the activator protein acts in vitro as a glycosphingolipid transfer protein, transporting glycosphingolipids from donor to acceptor liposomes. Lipids having less than three hexoses, e.g. galactosylceramide, sulfatide and ganglioside GM3 were transferred at very slow rates, whereas complex lipids such as gangliosides GM2, GM1 and GD1a were transferred much faster than the former. The transfer rate increased with increasing length of the carbohydrate chain of the lipid molecules. 3. Both the acyl residue in the ceramide moiety and the nature of the carbohydrate chain are significant for recognition of the glycosphingolipids by the sulfatide activator protein. Apparently, both residues serve as an anchor and the longer they are the better they are recognized by the protein. 4. In the absence of activator protein, degradation rates of sulfatide derivatives by arylsulfatase A, and of ganglioside GM1 derivatives by beta-galactosidase, increase with decreasing length of acyl residues in their hydrophobic ceramide moiety. Addition of activator protein stimulates the degradation of only those GM1 and sulfatide derivatives that have long-chain fatty acids in their hydrophobic ceramide anchor.
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PMID:Glycosphingolipid specificity of the human sulfatide activator protein. 188 21

Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed.
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PMID:Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases. 190

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

Human beta-galactosidase precursor mRNA is alternatively spliced into an abundant 2.5-kb transcript and a minor 2.0-kb species. These templates direct the synthesis of the classic lysosomal beta-D-galactosidase enzyme and of a beta-galactosidase-related protein with no enzymatic activity. Mutations in the beta-galactosidase gene result in the lysosomal storage disorders GM1-gangliosidosis and Morquio B syndrome. To analyze the genetic lesions underlying these syndromes we have isolated the human beta-galactosidase gene and determined its organization. The gene spans greater than 62.5 kb and contains 16 exons. Promoter activity is located on a 236-bp Pst I fragment which works in a direction-independent manner. A second Pst I fragment of 851 bp located upstream from the first negatively regulates initiation of transcription. The promoter has characteristics of a housekeeping gene with GC-rich stretches and five potential SP1 transcription elements on two strands. We identified multiple cap sites of the mRNA, the major of which maps 53 bp upstream from the translation initiation codon. The portion of the human pre-mRNA undergoing alternative splicing is encoded by exons II-VII. Sequence analysis of equivalent mouse exons showed an identical genomic organization. However, translation of the corresponding differentially spliced murine transcript is interrupted in its reading frame. Thus, the mouse gene cannot encode a beta-galactosidase-related protein in a manner similar to the human counterpart. Differential expression of the murine beta-galactosidase transcript is observed in different mouse tissues.
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PMID:Organization of the gene encoding human lysosomal beta-galactosidase. 190 71

The composition of whole embryo gangliosides at embryonic day E-12 was compared among the C57BL/6 (B6) DBA/2 (D2), and C3H mouse strains. N-acetylneuraminic acid was the predominant sialic acid species in the E-12 embryos. N-glycolyneuraminic acid was either undetectable or present in only trace amounts. Whole embryo ganglioside sialic concentration was significantly lower in D2 embryos than in B6 or C3H embryos. GM3 and GD3 were the most abundant ganglioside species in each strain and comprised approximately 75% of the total distribution. The D2 embryos expressed an elevation of GD1a and a reduction of GQ1b relative to B6 and C3H. Also, the level of GM1 was significantly higher in the D2 embryos than in the B6 or C3H embryos. Since a reduction of beta-galactosidase activity and an elevation of GM1 concentration in brain were previously reported in postnatal DBA mice, our results suggest that the elevated GM1 in D2 embryos may result from a reduced activity of GM1 beta-galactosidase.
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PMID:Ganglioside GM1 elevation in DBA/2 mouse embryos. 211 May 23

In an autopsy case of galactosialidosis, GM3, GM2, GM1, and GD1a were accumulated in sympathetic and spinal ganglia and grey matter of the spinal cord. Especially, the accumulations of GM3 and GM2 amounted to 41- and 86-fold increases in sympathetic ganglia, respectively, as compared to normal controls. In addition LacCer, GA2 and GA1 were accumulated in sympathetic and spinal ganglia. The accumulations of GM3 and GD1a are considered to be the result of defective lysosomal sialidase activity and the accumulation of GM1, LacCer and GA1 is also considered to be due to decreased beta-galactosidase activity in this disorder. To better understand the possible mechanism of GM2 accumulation, we determined the activity of GM2 synthesizing enzyme (GM3:UDP-GalNAc transferase), as well as hexosaminidase activity, in sympathetic ganglia, but they did not change. Abnormal ganglioside and neutral glycosphingolipid metabolism, as well as sialyloligosaccharide and sialylglycoprotein metabolism, may be involved in the pathogenesis of this disorder.
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PMID:Abnormal glycosphingolipid metabolism in the nervous system of galactosialidosis. 211 76

COS-1 cells were transfected by electroporation with a cDNA for human acid beta-galactosidase cloned in our laboratory and stable transformants expressing the enzyme activity were selected. The precursor form of the enzyme was secreted in large quantities into the culture medium. The fibroblasts from patients with GM1-gangliosidosis or Morquio B disease showed a remarkable increase of enzyme activity, up to the normal level, after culture in this medium for 2 days; the amount of uptake was essentially the same as that for the precursor form in human fibroblasts. After endocytosis, the precursor molecules were processed normally to the mature form and remained as stable as those produced by human fibroblasts. On the other hand, cells from galactosialidosis patients did not show any increase of enzyme activity in a similar experiment. It was concluded that the transformants are useful as the source of precursor proteins for the study of intracellular turnover of enzyme molecules in mutant cells.
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PMID:Beta-galactosidase-deficient human fibroblasts: uptake and processing of the exogenous precursor enzyme expressed by stable transformant COS cells. 212 39

GM1-gangliosidosis is a rare neurovisceral storage disease caused by an inherited deficiency of acid beta-galactosidase. The characteristic neurological feature of type 3 (adult or chronic) GM1-gangliosidosis is usually a slowly progressive dystonia with dysarthria due to predominant involvement of basal ganglia. About 20 adult patients with this disorder have been reported in the literature. However, there are no reports of 3 brothers with type 3 GM1-gangliosidosis, and MRI findings. Case 1 (proband): A 28-year-old man was hospitalized because of facial grimace, dysarthria, and generalized dystonia. He was born after normal pregnancy and delivery. His development was normal until 3 years of age when the difficulties of speaking and walking were noticed by his parents. These neurological abnormalities progressed slowly and facial grimace and dystonic movements occurred 7 years later. He could not walk at 22 years of age. On admission, he was bedridden with marked scoliosis and subluxation of the mandibule. The communication was possible only by pointing the words written on the board. Case 2: A 33-year-old man, elder brother of case 1, showed the similar neurological features and clinical course. Slit-lamp examination revealed corneal opacities which were located in the deep stroma. Case 3: A 33-year-old man, elder brother of case 1 or case 2. At age 10-11, he noted similar symptoms as case 1 or case 2. The severity of dystonia was milder than his brothers. A diagnosis of GM1-gangliosidosis in three patients was made on the basis of the following data.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Three siblings with type 3 GM1-gangliosidosis--pathophysiology of dystonia and MRI findings]. 212 60

Allogeneic bone marrow transplantation was carried out in an 81-day-old Portuguese water dog with GM1 gangliosidosis using a DLA identical sibling as donor. Engraftment was complete and beta-galactosidase activity in leukocytes of the transplanted dog were similar to those in the donor. Over the next 2.5 months neurological deterioration in the transplanted dog was similar to that in untreated dogs with GM1 gangliosidosis. Cerebral ganglioside GM1 concentrations were not diminished by bone marrow transplantation and cerebral beta-galactosidase activity was negligible. We conclude that allogeneic bone marrow transplantation early in life is ineffective in canine GM1 gangliosidosis.
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PMID:Bone marrow transplantation in canine GM1 gangliosidosis. 212 50

Saposins are small glycoproteins which are required for sphingolipid hydrolysis by lysosomal hydrolases. Each saposin (A, B, C, and D) stimulates a different enzymatic activity. A new simple HPLC method to determine the levels of saposins A, C, and D in tissue was developed. Tissues were homogenized in 20 vol of water, boiled, and centrifuged. The supernatant was lyophilized and redissolved in 5 ml of water. A 1.5-ml sample of the solution was applied to a reverse-phase HPLC column (C4 column) and eluted with an acetonitrile gradient. Most contaminants eluted from the column prior to the saposins, which were eluted later as a cluster of peaks. This cluster was collected and then analyzed by another HPLC system equipped with an AX-300 anion-exchange column using a NaCl gradient. Saposins D, A, and C eluted from the AX-300 column separately and in that order. Quantitation of the saposins was made by measuring the sizes of each peak. Standard curves made from pure saposins showed that quantification was linear over a range from 1 to 5 micrograms. Saposin B was measured by its stimulation activity on pure human liver GM1 ganglioside beta-galactosidase. Stimulation was linear up to 80 micrograms of saposin B. Application of this method to analysis of human tissues for their saposin content is presented.
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PMID:Determination of saposin proteins (sphingolipid activator proteins) in human tissues. 212 57


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