Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During a study of the gene coding for alpha-galactosidase (EC 3.2.1.22), the lysosomal enzyme deficient in Fabry's disease, RT-PCR amplification of alpha-galactosidase mRNAs obtained from three different tissues isolated from males revealed a substantial number of clones with a U to A conversion at the nucleotide position 1187. Such a modification of the coding sequence would result in an amino acid substitution in the C-terminal region (Phe396Tyr) of the enzyme. Neither PCR analysis of the genomic sequence nor the RT-PCR amplification of RNA obtained by in vitro transcription of the wild-type cDNA showed this change in the sequence. Multiple genes, pseudogenes are allelic variants were excluded. Hence, we propose RNA editing as a mechanism responsible for this base change in the alpha-galactosidase RNA.
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PMID:Editing of human alpha-galactosidase RNA resulting in a pyrimidine to purine conversion. 750 18

The effect of galactose on alpha-galactosidase missense mutants causing Fabry disease was investigated in the COS-1 cell expression system and lymphoblasts. Three mutant enzymes, A156V, L166V and Q279E, showed increases in activity and amount in COS-1 cells cultured with galactose. Another mutant without catalytic activity, C142Y, did not show any changes. In lymphoblasts cultured with galactose, the enzyme activity increased significantly in four classical Fabry patients with the respective mutations, A156V, L166V, G260A and G373S, and in three atypical Fabry patients with the respective mutations, Q279E, R301Q and M296I. Such an increase was not observed in the other four classical Fabry patients, with C142Y, E66Q/R112C, G328R and N320K, respectively. This suggests that many missense mutations in the alpha-galactosidase gene causing Fabry disease allow the expression of catalytically active mutant enzymes regardless of the clinical phenotype, which are rapidly degraded under physiological conditions and stabilized by galactose.
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PMID:Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. 757 33

Our previous study on chimeric mutants of alpha-galactosidase suggested that two peptide regions encoded by exons 1-2 and 6 of the enzyme gene contribute to substrate recognition (Ishii, S. et al. (1994) Biochim. Biophys. Acta 1204, 265-270). In this study, we constructed five single amino acid substitutions for functional analysis of the amino acid residues around glutamine-279, the mutation site detected in an atypical Fabry disease patient. Two mutants, Q280S (Gln280-->Ser; CAA-->TCA) and T282A (Thr282-->Ala; ACT-->GCT), showed increased Km and decreased thermostability as compared with normal enzyme. Circular dichroism spectrum was not modified. An additional chimeric mutation in the exon 1-2 region by substitution with the homologous sequence of alpha-N-acetylgalactosaminidase cDNA restored catalytic activity and thermostability in both mutants. These data indicated the functional significance of glutamine-280 and threonine-282 for expressing the activity and stability of alpha-galactosidase molecule, and also the presence of an intramolecular interaction between the two peptide regions encoded by exons 1-2 and 6.
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PMID:The functional role of glutamine-280 and threonine-282 in human alpha-galactosidase. 772 39

Fabry's disease is a rare hereditary disease transmitted as an X-linked recessive trait with the primary metabolic defect of an enzyme alpha-galactosidase A, resulting in deposition of glycolipids (ceramide trihexoside) in various tissues, including the kidneys. Two sibling cases of Chinese adult male patients in a family with Fabry's disease were completely evaluated including the clinical, pathologic and biochemical studies. Both of the patients had the similar clinical manifestations such as telangiectases, proteinuria, acral pains, corneal opacities, tortuous renal vessels and recurrent fever. Chronic renal insufficiency was noted in Case 1, whereas Case 2 had normal renal function. Microscopic hematuria was noted in Case 1. In renal biopsy, LM showed foamy vacuolation of the glomerular visceral epithelial cells and EM showed widespread myelin bodies (Zebra bodies) in kidney tissues, most numerous in visceral epithelia in both cases. Those findings are diagnostic for Fabry's disease. The plasma activity of alpha-galactosidase of Case 1 was 0.8 and that of Case 2 was 1.0 (normal reference range: 8.5-18.5 nmol/hr/min). The plasma activity of alpha-galactosidase A of Case 1 was 0.4 and that of Case 2 was 0.8 (normal reference range: 7.9-16.9 nmol/hr/min). All the enzyme activities in both cases were much lower than those of normal subjects. In addition to clinical presentations, pathologic study and biochemical study with assays of plasma or serum activities of alpha-galactosidase and alpha-galactosidase A are important steps in the diagnosis of Fabry's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fabry's disease: clinical, pathologic and biochemical manifestations in two Chinese males. 783 62

The expression product of a mutant alpha-galactosidase gene, Q279E (279Gln-->Glu), found in an atypical variant (cardiac form) of Fabry disease, was purified and characterized. It had kinetic properties similar to those of normal alpha-galactosidase, but was markedly thermolabile at neutral pH. Galactose and melibiose at high concentrations stabilized the mutant enzyme in vitro. Its catalytic activity was 15% of that for the normal enzyme, when it was expressed in COS-1 cells at 37 degrees C. The activity increased at 30 degrees C or in the presence of galactose at 37 degrees C. An increase was also observed in lymphoblasts from a patient with this mutation in the presence of galactose or melibiose. We conclude that this mutant protein is posttranslationally inactivated under the neutral conditions in the cells. The possibility of a new therapeutic approach is suggested.
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PMID:Characterization of a mutant alpha-galactosidase gene product for the late-onset cardiac form of Fabry disease. 790 61

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Patients with classic Fabry disease of early onset show diverse clinical manifestations caused by generalized vasculopathy. Recent clinical and enzymatic examinations have revealed another form of this disease; progressive cardiomyopathy of late onset without other systemic signs or symptoms. Efforts were directed to identify the specific mutations in the alpha-galactosidase gene and to clarify the phenotype/genotype correlations. A variety of mutations, including deletions, nonsense mutations, splicing mutations and amino acid substitutions caused the classic form of Fabry manifestations, which resulted in the complete deficiency of alpha-galactosidase activity. Single base substitutions were detected in the upstream region of alpha-galactosidase gene exon 6, which resulted in residual enzyme activity. The degree of the expressed residual enzyme activity might determine the clinical phenotypes. Heterozygotes were successfully identified by gene analysis and immunofluorescence imaging diagnosis using confocal laser scanning microscopy.
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PMID:[Molecular genetics of inherited metabolic diseases--its application to the investigation of pathogenesis and the diagnosis of Fabry disease]. 791 43

Human alpha-galactosidase A (alpha-D-galactoside galactohydrolase; EC 3.2.1.22), the glycosylated lysosomal enzyme deficient in Fabry disease, has been crystallized as a complex with the inhibitor N-6-aminohexanoyl-alpha-D-galactopyranosylamine. The "hanging drop" method of vapor diffusion was used to grow crystals from solutions containing 50 mM sodium phosphate (pH 4.0 to 4.5), 120 to 170 mM ZnCl2 and 8 to 10% polyethylene glycol 3350. X-ray diffraction data collected from these crystals indicate that the crystals belong to the orthorhombic space group C222(1) with cell dimensions of a = 93.8 A, b = 141.1 A and c = 184.4 A. The crystals diffract to a resolution of 3 A and native data have been collected to 3.5 A resolution. Assuming one dimer per asymmetric unit with a total molecular mass of 110 kDa (with oligosaccharide chains), the Matthews' coefficient is Vm = 2.77 A3/dalton corresponding to a solvent content of 55% (v/v). The self-rotation function reveals that a non-crystallographic 2-fold axis relates the subunits of each dimer.
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PMID:Crystallization and preliminary X-ray analysis of human alpha-galactosidase A complex. 800 70

Human umbilical venous endothelial cells were transformed with a temperature-sensitive mutant of simian virus 40, tsA640, and a cell line, subcultured for over 20 serial passages, was established at a temperature permissive for the virus. Treatment of transformed endothelium with 3 micrograms/ml chloroquine caused a specific reduction of alpha-galactosidase activity, without cell injury, and revealed several electron-dense materials surrounded by single unit membranes. Crystalline lamellae in lysosomes with a periodicity of 6.5 nm, which are typically seen in various tissues in Fabry disease, were produced in the presence of a glycosphingolipid mixture. These cells should be useful for in vitro pathophysiological studies on Fabry endothelium.
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PMID:Lysosomal glycosphingolipid storage in chloroquine-induced alpha-galactosidase-deficient human endothelial cells with transformation by simian virus 40: in vitro model of Fabry disease. 838 72

There are no reports of anesthesia for a patient with Fabry's Disease in Japan. Fabry's Disease is a rare hereditary disease that is characterized by alpha-galactosidase deficiency caused by deposition of glycolipid in many organs. The disease may be complicated by cardiac ischemic disease, neurological disorder and renal failure. The patient is a 45-year-old female with cholelithiasis who underwent cholecystectomy. This patient had been hospitalized repeatedly for the past 15 years because of the chronic pyelits, and hyperglycemia, and nephrosis. She developed chronic renal failure, hemodialysis was started when diagnosis of Fabry's Disease was made at age of 41. Preoperative electrocardiogram revealed ischemic change on leads II, V5 and V6. Nifedipine was administered for hypertension. The anesthesia was induced with thiopental followed by vecuronium for endotracheal intubation, and maintained with nitrous oxide, oxygen and isoflurane. Accompanied by nicardipine for hypertension, and vecuronium for muscle relaxation using a neurotransmission monitor (Relaxograph), nitroglycerin was continuously infused. We avoided the effect of atropine for reversal of muscle relaxation because most of the patients were complicated with hypohidrosis. During administration of nitroglycerin and nicardipine, the neuromuscular blocking effects of vecuronium could be prolonged. The neuromuscular monitoring was useful in this case.
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PMID:[The anesthetic management of a patient with Fabry's disease]. 852 62

alpha-Galactosidase A (alpha-D-galactoside galactohydrolase, EC 3.2.1.22; alpha GalA) is a lysosomal enzyme that hydrolyses the alpha-D-galactosyl residues from glycosphingolipids. Fabry disease, an inhibited X-linked recessive human metabolic disorder, results from a mutation in the alpha GalA gene at Xq22. As a prerequisite for generating a mouse model of Fabry disease by gene targeting, we have isolated and characterized the mouse alpha GalA gene and cDNA. A cloned mouse alpha GalA cDNA encoded a putative precursor protein of 419 amino acids (aa), including a 31-aa signal peptide (SP). The deduced aa sequence showed high homology (79%) with the human alpha GalA protein. Nucleotide sequence analysis of genomic clones revealed that the overall structure and organization of the gene was very similar to that of human alpha GalA. All exon-intron splice junctions conformed to the GT/AG consensus sequence. Comparison of genomic and cDNA sequences revealed the occurrence of two putative polyadenylation signals whose alternative use results in the two mouse alpha GalA transcripts of 1.4 and 3.6 kb. The 5'-flanking region of mouse alpha GalA had no typical TATA box. Several putative promoter-associated elements including Sp1, AP1 and a potential cAMP-responsive element (CRE) were identified. Northern blot analysis revealed the widespread tissue distribution of mouse alpha GalA transcripts. Lower expression levels, however, were observed in some tissues, implying tissue-specific differences in alpha GalA promoter function.
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PMID:Structural organization and expression of the mouse gene encoding alpha-galactosidase A. 854 75


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