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)

Clinical findings were compared with the results of molecular analysis in 16 Japanese patients from 10 unrelated families with the adult/chronic form of GM1 gangliosidosis. Age of onset ranged from 3 to 30 years. Major clinical manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic postures and movements, facial grimacing, and parkinsonian manifestations were commonly seen. Cerebellar signs, myoclonus, severe intellectual impairment, dysmorphism, or visceromegaly were not observed. A common single-base substitution, 51Ile(ATC)----Thr(ACC), reported in a previous study of ours, was confirmed in 14 patients by the Bsu36I restriction site analysis; one was a compound heterozygote with another mutation (457Arg[CGA]----Gln[CAA]) and the others were homozygotes of this mutation. Clinically, the compound-heterozygous patient showed more severe neurological manifestations and a more rapid clinical course than those of homozygotes. The homozygotes showed considerable variations in the age of onset and subsequent clinical course. The 51Ile----Thr mutant allele expressed a significant amount of beta-galactosidase activity, whereas the 457Arg----Gln mutant allele expressed extremely low activity in human GM1 gangliosidosis fibroblasts. We conclude that these gene mutations causing different residual enzyme activities are related to the severity of clinical manifestations, but some other genetic or environmental factors contribute to clinical heterogeneity. The Bsu36I restriction site analysis was performed in 7 families and provided clear results for the diagnosis of heterozygotes as well as homozygotes of this specific clinical form of GM1 gangliosidosis. The technique is applicable to prenatal diagnosis and genetic counseling.
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PMID:GM1 gangliosidosis in adults: clinical and molecular analysis of 16 Japanese patients. 135 43

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

Apolipoprotein (apo) B-100 is the major protein component in low density lipoprotein (LDL); it contains the binding domain for the LDL receptor and the attachment site for apolipoprotein(a) in lipoprotein(a). ApoB-48 is colinear with the amino-terminal half of apoB-100 and misses the part of the molecule required for LDL receptor interaction and lipoprotein(a) formation. ApoB-48 mRNA is produced by the editing of apoB-100 mRNA, a process by which the codon CAA for Gln-2153 is changed to UAA, an in-frame stop codon. We used the cloned catalytic component of the rat apoB mRNA-editing enzyme (REPR) to construct a replication-defective recombinant adenoviral vector containing REPR cDNA (AvREPR) and a control vector (Av1LacZ4) containing a beta-galactosidase cDNA to investigate the effect of REPR gene delivery in C57BL/6 mice. Intravenous injection of AvREPR in mice resulted in efficient transduction of liver cells, where REPR mRNA and protein were overexpressed, reaching a peak at 7 and 12 days, returning toward control levels at 39 days after AvREPR administration. ApoB mRNA editing activity in liver extracts showed changes parallel to those of REPR mRNA expression; the proportion of edited apoB mRNA in the total hepatic apoB mRNA increased from approximately 60% to more than 90% at the peak of REPR expression. The proportion of plasma apoB-100 in AvREPR-transduced animals decreased from approximately 50% to < 10% of total plasma apoB concentration. Plasma very low density lipoproteins were polydisperse in control animals with an average diameter of 54.9 +/- 20.6 nm (uninjected control) and 54.7 +/- 16.8 nm (Av1LacZ4-treated), respectively. They became much smaller (average diameter 39.3 +/- 12.7 nm) and more uniform in size at day 12 following AvREPR administration. On the same day, the normal plasma LDL (26.2-25.5 nm) was almost completely eliminated in treated animals. Adenovirus-mediated transfer of the REPR cDNA is an efficient method to reduce plasma apoB-100 and normal LDL production.
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PMID:Adenovirus-mediated gene transfer of rat apolipoprotein B mRNA-editing protein in mice virtually eliminates apolipoprotein B-100 and normal low density lipoprotein production. 796 18

In order to study the conversion of UV lesions into frameshift and base substitution mutations, M13mp2 phage DNA was altered by the addition of extra pyrimidines, or by construction of a nonsense codon preceded by a run of pyrimidines within the beta-galactosidase complementing region. The normal sequence 5' GTC GTT TTA CAA 3' was changed to GTC GTT T TTA CAA (MIDT) or GTC GTT C TTA CAA (MIDC) to study frameshifts and to GTC GTT CTT TAA (OCHRE) to study reversion of the ochre (TAA) codon. Escherichia coli pol I Kf and T7 DNA polymerase mutant enzymes devoid of 3'-->5' exonuclease activity produced UV-induced revertants at higher frequency than did their exonuclease proficient counterparts. Removal of cyclobutane dimers with photolyase before in vitro synthesis did not greatly affect mutant frequency although such treatment led to significantly increased DNA synthesis by the wild-type T7 DNA polymerase on UV-irradiated substrate. Reversions of the in frame ochre sequence GTT CTT TAA produced by the delta 28 T7 DNA polymerase were mainly by base substitution in the TAA codon. About half of the E. coli Kf exo- enzyme ochre revertants had a TTA deletion. Five mutant T7 DNA polymerases with varying exonuclease activity gave revertant frequencies that correlated better with published values of enzyme velocity than with exonuclease activity or with measured bypass synthesis. Our data indicate that loss of proofreading activity increases the frequency of UV-induced frameshifts, but lack of such activity is not sufficient for their production. We suggest that frameshifts occur more frequently when nucleotide addition opposite the lesion is slow. The same lesion can give rise to a different spectrum of mutations depending on the polymerase.
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PMID:Production of UV-induced frameshift mutations in vitro by DNA polymerases deficient in 3'-->5' exonuclease activity. 802 6

Cerebral amyloid angiopathy (CAA) caused by amyloid beta (Abeta) deposition around brain microvessels results in vascular degenerative changes. Antiangiogenic Abeta properties are known to contribute to the compromised cerebrovascular architecture. Here we hypothesize that Abeta peptides impair angiogenesis by causing endothelial cells to enter senescence at an early stage of vascular development. Wild-type (WT) Abeta and its mutated variant E22Q peptide, endowed with marked vascular tropism, were used in this study. In vivo, in zebrafish embryos, the WT or E22Q peptides reduced embryo survival with an IC(50) of 6.1 and 4.7 microM, respectively. The 2.5 microM concentration, showing minimal toxicity, was chosen. Alkaline phosphatase staining revealed disorganized vessel patterning, narrowing, and reduced branching of vessels. Beta-galactosidase staining and the cyclin-dependent kinase inhibitor p21 expression, indicative of senescence, were increased. In vitro, WT and E22Q reduced endothelial cell survival with an IC(50) of 12.3 and 8.8 microM, respectively. The 5 microM concentration, devoid of acute effects on the endothelium, was applied chronically to long-term cultured human umbilical vein endothelial cells (HUVECs). We observed reduced cumulative population doubling, which coincided with beta-galactosidase accumulation, down-regulation of telomerase reverse-transcriptase mRNA expression, decreased telomerase activity, and p21 activation. Senescent HUVECs showed marked angiogenesis impairment, as Abeta treatment reduced tube sprouting. The endothelial injuries caused by the E22Q peptide were much more aggressive than those induced by the WT peptide. Premature Abeta-induced senescence of the endothelium, producing progressive alterations of microvessel morphology and functions, may represent one of the underlying mechanisms for sporadic or heritable CAA.
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PMID:Abeta peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis. 2020 41