Characterization of glucocerebrosidase in Greek Gaucher disease patients: mutation analysis and biochemical studies
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Gaucher disease is the most frequent lysosomal storage disease in Greece, accounting for 24% of all lysosomal disorders diagnosed during the last 13 years at the Institute of Child Health in Athens. The nature of the defects in glucocerebrosidase in Greek Gaucher patients with non-neuronopathic (type 1) and neuronopathic (types 2 and 3) phenotypes was investigated at the level of the glucocerebrosidase gene and enzyme activity. Mutation analysis performed in 10/23 Gaucher patients with different types of the disorder led to the identification of four mutations, N370S, L444P, R463C and D409H, comprising 75% of the investigated alleles. N370S was only found in association with type 1 disease. The genotype D409H/R463C was identified for the first time and was associated with the severe type 2 disorder. There was no correlation between residualin vitro enzyme activity and either phenotype or genotype. However, in cultured fibroblasts of the neuronopathic cases, glucocerebrosidase protein concentration was reduced and the capacity to degrade exogenous C6NBD-glucosylceramide was more severely impaired.
- Aerts JMFG, Donker-Koopman WE, van der Vliet MK, et al (1983) The occurrence of two immunologically distinguishable β-glucocerebrosidases in human spleen.Eur J Biochem 130: 565–574. CrossRef
- Agmon V, Cherbu S, Dagan A, Grace M, Grabowski GA, Gatt S (1993) Synthesis and use of novel fluorescent glucosphingolipids for estimating β-glucosidase activityin vitro in the absence of detergents and subtyping Gaucher disease variants following administration into intact cells.Biochim Biophys Acta 1170: 72–79.
- Barranger JA, Ginns EI (1989) Glucosylceramide lipidoses: Gaucher disease. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic Basis of Inherited Diseases, vol II. McGraw-Hill, New York, 1677–1698.
- Beutler E, Gelbart T, West C (1990) The facile detection of the nt 1226 mutation of glucocere-brosidase by mismatched PCR.Clin Chm Acta 194: 161–166. CrossRef
- Beutler E, Gelbart T, Kuhl W, Sorge J, West C (1991) Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state.Proc Natl Acad Sci USA 88: 10544–10547. CrossRef
- Beutler E, Gelbart T, Kuhl W, Zimran A, West C (1992) Mutations in Jewish patients with Gaucher disease.Blood 79: 1662–1666.
- Fabbro D, Desnick RJ, Grabowski GA (1986) Gaucher disease: Genetic heterogeneity within and among the subtypes detected by immunoblotting.Am J Hum Genet 40: 4015–4031.
- Gaucher PCE (1882)De l'epithelioma primitif de la rate, hypebrophie indiopathique de la rate sans leucemie. Thesis, Paris.
- Ginns EE, Choundary PV, Martin B, et al (1984) Isolation of cDNA clones for human β-glucocere-brosidase using λ-gt 11 expression system.Biochem Biophys Res Commun 123: 574–580.
- Grabowski GA, Goldblatt J, Dinur T, et al (1985) Genetic heterogeneity in Gaucher disease: Physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients.Am J Med Genet 21: 529–549. CrossRef
- Horowitz M, Zimran A (1994) Mutations causing Gaucher disease.Hum Mutat 3: 1–11. CrossRef
- Jonsson LMV, Murray GJ, Sorrell S, et al (1987) Biosynthesis and maturation of glucocerebrosidase in Gaucher fibroblasts.Eur J Biochem 164: 171–179. CrossRef
- Latham T, Grabowski GA, Theophilus BD, Smith GI (1990) Complex alleles of the acid β-glucosi-dase gene in Gaucher's disease.Am J Hum Genet B45: 79–80.
- Michelakakis H, Dimitriou E, Tsagarakis S, Giouroukos S, Schulpis K, Bartsocas CS (1995) Lysosomal storage diseases in Greece.Genet Counselling 6(1): 43–47.
- Mistry PK, Cox TM (1993) The glucocerebrosidase locus in Gaucher's disease: molecular analysis of a lysosomal enzyme.J Med Genet 30: 889–894. CrossRef
- Ohashi T, Hong CM, Weiler S et al (1991) Characterization of human glucocerebrosidase from different mutant alleles.J Biol Chem 266:3661–3667.
- Sorge J, West C, Westwood B, Beutler E (1985) Molecular cloning and nucleotide sequence of human glucocerebrosidase cDNA.Proc Natl Acad Sci USA 82: 7289–7293. CrossRef
- Theophilus BM, Latham T, Grabowski GA, Smith FZ (1989) Comparison of RNase A, chemical cleavage and GC-clamped denaturing gel electrophoresis for the detection of mutations in exon 9 of the human acid β-glucosidase gene.Nucl Acids Res 17: 7707–7722.
- Van Weely S, Van Leeuwen MB, Jansen IDC, et al (1991) Clinical phenotypes of Gaucher disease in relation to properties of mutant glucocerebrosidase in cultured fibroblast.Biochim Biophys Acta 1096: 301–311.
- Zimran A, Horowitz M (1993) RecTL — a complex allele in the glucocerebrosidase gene associated with a mild clinical course of Gaucher disease.Second International Duodecim Symposium on ‘Molecular Biology of Lysosomal Disorders’, Helsinki.
- Zimran A, Abrahamov A, Gross-Zur V, et al (1993) A unique form of Gaucher disease in Arabs, characterised by occulomotor apraxia and valvular heart disease.Second International Duodecim Symposium on ‘Molecular Biology of Lysosomal Disorders’, Helsinki.
- Characterization of glucocerebrosidase in Greek Gaucher disease patients: mutation analysis and biochemical studies
Journal of Inherited Metabolic Disease
Volume 18, Issue 5 , pp 609-615
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- 1. Department of Enzymology and Cellular Function, Institute of Child Health, Children's Hospital ‘Ag. Sophia’, 11527, Athens, Greece
- 2. E. C. Slater Institute, University of Amsterdam, The Netherlands