title: [alpha-Galactosidase gene mutation and its expression product in Fabry disease (alpha-galactosidase deficiency)].
abstract: Fabry disease is characterized by a deficiency of lysosomal alpha-galactosidase (alpha-Gal) and the accumulation of glycosphingolipid (e.g. predominantly globotriaosylceramide) in various tissues, mainly in lysosomes of the vascular endothelium. This disorder is currently classified into two clinical phenotypes; classical severe type and atypical variant type. Classical form patients, with clinical manifestations of generalized angiopathy of early onset, usually show no detectable alpha-Gal activity. Recently, there are also atypical form patients with residual alpha-Gal activity and late-onset cardiomyopathy without other systemic manifestations. So far, we identified a number of alpha-Gal gene mutations including partial gene deletions, splicing mutations, nonsense mutations and missense mutations. They were heterogeneous and more than half of them were missense mutations. To clarify the molecular mechanism causing the enzyme defect in the patient, various missense mutations were expressed in COS-1 cells. At least, two groups have been identified; one expressing a mutant enzyme without catalytic activity (non-functional type), and the other expressing catalytically active but unstable mutant enzyme (fragile type). The fragile type mutants were widely present in the different clinical phenotypes from classical severe type to atypical milder type including subclinical Fabry hemizygote, and the mutant enzymes were posttranslationally inactivated and degraded in the cells. The inactivation and degradation were prevented by the addition of substrate analogue; galactose or melibiose. These findings provided us with significant informations on the molecular pathology of the enzyme defect in Fabry disease, and suggested the possibility of a new therapeutic approach for this disease.
authors.affiliation: Department of Clinical Laboratory Medicine, Kochi Medical School, Nankoku.
authors.forename: T
authors.initials: T
authors.lastname: Okumiya
authors.forename: T
authors.initials: T
authors.lastname: Takata
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: H
authors.initials: H
authors.lastname: Sakuraba
mesh_terms: D000795:Fabry Disease / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase