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

Polyethylene glycol-1000 (PEG-1000) induced fusion of HPRT (E.C. 2.4.2.8) deficient Chinese hamster cells with alpha-galactosidase A (E.C. 2.3.1.22) deficient cells from a patient with Fabry's disease yielded hybrids which contained both human and hamster HPRT, G6PD (E.C. 1.1.1.49), and APRT (E.C. 2.4.2.7) and Chinese hamster alpha-galactosidase B. Thus PEG-1000 mediated somatic cell fusion led to reexpression of Chinese hamster HPRT. It did not restore the expression of human alpha-galactosidase. Since PEG-1000 treatment of HPRT- Chinese hamster cells in the absence of human cells yielded no HPRT+ cells, it is concluded that the element responsible for the restoration of rodent HPRT was contributed by the human cells and not by the agent employed to promote fusion.
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PMID:Reexpression of HPRT activity following cell fusion with polyethylene glycol. 20 82

The enzymatic diagnosis of hemizygotes with Fabry disease and heterozygous carriers was accomplished by the fluorometric determination of alpha-galactosidase activities in tears. Two components of total alpha-galactosidase activity were differentiated by their relative thermostabilities and by chromatography on DEAE-cellulose. The major component, alpha-galactosidase A, was thermolabile and represented approximately 90% of total activity; the remaining activity was thermostable, eluted at a slightly higher salt concentration and was designated alpha-galactosidase B. A single, symmetric pH optimum was observed for total alpha-galactosidase activities from heterozygotes and normal individuals, whereas the total activity from hemizgotes, which was about 10% of that in normal controls, had a broad pH profile, identical to those for alpha-galactosidase B activities from all individuals studied. The apparent Km values for total activities were 3.2, 4.0, and greater than 13 mM for normal individuals, heterozygotes, and hemizygotes, respectively. In contrast, apparent Km values for alpha-galactosidase B activities were greater than 13 mM for all individuals, further suggesteng that the residual activity in hemizygotes with Fabry disease represented the alpha-galactosidase B component. of the potential inhibitors studied, alpha-D-melibiose was found to competitively inhibit total alpha-galactosidase activity (Ki approximately 10 mM). These studies demonstrate that tears provide an easily obtainable source of freshly secreted enzyme for the diagnosis of hemizygotes and heterozygotes with Fabry disease and suggest that tears may be useful for the diagnosis of other inborn errors of metabolism.
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PMID:Fabry disease: diagnosis by alpha-galactosidase activities in tears. 24 13

1. A method is described for the rapid isolation of alpha-galactosidases A and B (alpha-D-galactoside galactohydrolase, EC 3.2.1.22) from normal human liver. 2. When the same method is applied to Fabry liver, most of the alpha-galactosidase activity is recovered in the fraction corresponding to normal alpha-galactosidase B. In agreement with Romeo, G., D'Urso, M., Pisacane, A., Blum, E., De Falco, A. and Ruffilli, A. (1975) Biochem. Genet. 13, 615-628) [18], a small amount of alpha-galactosidase activity is found in the fraction corresponding to normal alpha-galactosidase A. 3. The kinetic properties of the B-like activity from Fabry liver are similar to those of normal alpha-galactosidase B. In agreement with Romeo et al. [18], it was found that the kinetic properties of the A-like activity from Fabry liver are similar to those of normal alpha-galactosidase A. 4. Using antisera raised against normal alpha-galactosidase A and normal alpha-galactosidase B, it is shown that the normal alpha-galactosidase isoenzymes are immunologically distinct and that the B-like activity from Fabry liver is immunologically related to normal alpha-galactosidase B. Furthermore, the A-like activity from Fabry liver is immunologically related to normal alpha-galactosidase B and not to normal alpha-galactosidase A. 5. Normal alpha-galactosidase B is converted into an A-like form during storage. 6. It is concluded that the B-like alpha-galactosidase in Fabry tissues is identical to normal alpha-galactosidase B, and that the small amount of A-like activity found in Fabry material is due to a modified form of alpha-galactosidase B.
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PMID:Enzymological properties and immunological characterization of alpha-galactosidase isoenzymes from normal and Fabry human liver. 40 43

The properties of the residual alpha-galactosidase activity in kidney, liver, spleen, fibroblasts and urine of a Fabry hemizygote have been studied using p-nitrophenyl-alpha-galactoside and 4-methylumbelliferyl-alpha-galactoside as substrates. In addition, alpha-galactosidase activity in urine has been determined with ceramidetrihexoside as substrate. The residual alpha-galactosidase activity of Fabry, measured with artificial substrate, is stimulated (6-35%) by myo-inositol and only slightly inhibited by melibiose (7-17%) in all the materials used. In contrast, the alpha-galactosidase of normal tissues and urine is inhibited (36-48%) by myo-inositol and inhibited to a much greater extent (40-50%) by melibiose. The KM for artificial substrate of the residual activity of Fabry is higher than that of the alpha-galactosidase in normal kidney, liver, spleen, fibroblasts and urine. The residual activity of Fabry is generally more stable to heating than the activity in the normal materials, although exceptions were noted. When these properties are compared with those of the alpha-galactosidase isoenzymes in normal tissues and body fluids, the residual activity of Fabry material seems to be very similar to the minor component of normal tissue (alpha-galactosidase B). Moreover, the pH optimum curve of this minor component and of the Fabry alpha-galactosidase in urine are similar, whereas the major isoenzyme (alpha-galactosidase A) shows a curve much more like that of normal urine. The findings with ceramidetrihexoside as substrate indicate a possible discrepancy. Alpha-Galactosidase A hydrolyses ceramidetrihexoside, Fabry urine preparation does not. However, alpha-galactosidase B of normal urine shows a slight but definite ceramidetrihexosidase activity. No contamination of the B preparation with alpha-galactosidase A could be detected. The minimum hypothesis, supported by most of the experimental evidence, is that the residual activity of Fabry and normal alpha-galactosidase B are identical.
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PMID:Properties of the residual alpha-galactosidase activity in the tissues of a Fabry hemizygote. 80 16

The alpha-galactosidase A activity from fibroblasts of five Fabry patients and five controls has been separated from alpha-galactosidase B through small DEAE-cellulose columns and in some experiments by treatment of the fibroblast extracts with Sepharose coupled to anti-alpha-galactosidase B antibodies. By these independent methods, it has been shown that there is a residual alpha-galactosidase A in Fabry's disease, which is immunologically similar to the alpha-galactosidase A from the controls. The alpha-galactosidase A from all of the patients and controls has the same apparent Km value for the synthetic substrate 4-methylumbelliferyl-alpha-galactosidase A, while the fifth has a thermolabile enzyme like that from the controls. The amount of immunologically active alpha-galactosidase A seems to be decreased in the patients tested.
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PMID:Residual activity of alpha-galactosidase A in Fabry's disease. 81 85

Recently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman. Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. Investigation of the alpha-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of alpha-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait. Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. These studies document the occurrence of two forms of alpha-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides and the absence of detectable neurologic involvement.
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PMID:Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria. 190 16

Activities and multiple forms of alpha-D-galactosidase of human kidney and liver in the normal and in Fabry's disease were comparatively studied using alpha-D-galactoside and alpha-D-fucoside as substrates. By isoelectric focusing alpha-D-galactosidase was shown to exist in multiple forms, one of which possesses both alpha-D-galactosidase and alpha-D-fucosidase activity. In Fabry's disease, caused by a deficiency of alpha-D-galactosidase A, we found only one form of alpha-D-galactosidase, which corresponded to form B (alpha-N-acetylgalactosaminidase) and was also able to split alpha-D-fucoside. Thus, in Fabry's disease the alpha-D-fucosidase profile was virtually unchanged, as compared with the normal. The results obtained indicate that the alpha-D-fucosidase activity is due to the action of alpha-D-galactosidase B, encoded for by an autosomal gene of chromosome 22. We suppose these data could be confirmed by revealing the significant reduction of the alpha-D-fucosidase activity in patients with alpha-N-acetylgalactosaminidase deficiency.
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PMID:Relationship of the multiple forms of human alpha-D-galactosidase and alpha-D-fucosidase in the normal and in Fabry's disease. 216 Feb 80

A new method is described for the detection of abnormal urinary oligosaccharide and glycopeptide excretion by thin layer chromatography and differential visualization of oligosaccharides and glycopeptides. This method permits rapid screening and identification of disorders characterized by oligosacchariduria and glycopeptiduria including alpha-N-acetylgalactosaminidase deficiency, angiokeratoma corporis diffusum with glycopeptiduria, aspartylglucosaminuria, galactosialidosis, fucosidosis, GM1 gangliosidosis and sialidoses 1 and 2. Of note, the characterization of the glycopeptide excretion profiles in patients with alpha-N-acetylgalactosaminidase deficiency and angiokeratoma corporis diffusum with glycopeptiduria revealed essentially identical patterns, indicating the metabolic relatedness of these two phenotypically distinct conditions. Use of this improved thin layer chromatographic method should enhance routine screening of patients for lysosomal storage diseases as well as permit the identification of new disorders resulting from defective oligosaccharide and/or glycoprotein metabolism.
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PMID:A method for the rapid detection of urinary glycopeptides in alpha-N-acetylgalactosaminidase deficiency and other lysosomal storage diseases. 220 41

Human lymphoid cell lines established by Epstein-Barr viral transformation of peripheral B-lymphocytes from normal subjects and from Fabry patients, were investigated for their ability to biosynthesize neutral glycosphingolipids from [14C]galactose and [14C]glucose as precursors. Galactose was taken up in the presence of high concentrations of glucose and selectively utilised by the cells in the synthesis of galactosphingolipids. The pattern of neutral glycosphingolipids labelled from [14C]galactose was slightly modified with time of labelling in either lymphoid cell line: the first labelled glycosphingolipid was lactosylceramide (LacCer) in the normal line and globotetraosylceramide (GbOse4Cer) in the Fabry line. After labelling for 96 h, a steady state was reached and the percentage of every type of labelled glycosphingolipid was stable in each cell line; however, differences in the neutral sphingolipid composition appeared between the various cell lines. When using radiolabelled glucose as precursor, the major part of the radioactivity was incorporated into neutral lipids and phospholipids; neutral sphingolipids were much less labelled than when using galactose. Catabolism of endogeneous labelled glycosphingolipids (synthesized by the cells during the 'pulse') was studied after cultivating the cells without radiolabelled precursors ('chase'). In the cells from normal subjects, all the neutral glycosphingolipids were slowly degraded (half-life time around 15-25 days for LacCer and GbOse3Cer). In contrast, in a lymphoid line from a Fabry patient, no appreciable degradation of GbOse3Cer occurred during 30 days. This block in the catabolism of GbOse3Cer is in good agreement with the previously reported deficiency of alpha-galactosidase A activity in this Fabry lymphoid cell line [Salvayre, R. et al. (1981) Biochim. Biophys. Acta 659, 445-456] and demonstrates that alpha-galactosidase B does not hydrolyze GbOse3Cer in the living cell (in contrast to the situation in vitro).
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PMID:[Neutral glycosphingolipids of Fabry's disease lymphoblastoid lines established by Epstein-Barr virus transformation]. 298 12

A simple and sensitive fluorometric method has been described for the differential determination of the activity of lysosomal alpha-galactosidase A and alpha-galactosidase B. The procedure employs 4-methylumbelliferyl-alpha-D-galactopyranoside as substrate and N-acetylgalactosamine as an inhibitor of alpha-galactosidase B, but not of alpha-galactosidase A to differentiate the two activities. This method was shown to be applicable in the differentiation of the two enzyme activities in human tissues and in the diagnosis of the heterozygous and hemizygous genotypes for Fabry's disease in cultured skin fibroblasts.
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PMID:Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. 626 21


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