Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease

J Biol Chem. 1987 Feb 15;262(5):2062-5.


The synthesis and processing of the human lysosomal enzyme alpha-galactosidase A was examined in normal and Fabry fibroblasts. In normal cells, alpha-galactosidase A was synthesized as an Mr = 50,500 precursor, which contained phosphate groups in oligosaccharide chains cleavable by endoglucosaminidase H. The precursor was processed via ill-defined intermediates to a mature Mr 46,000 form. Processing was complete within 3-7 days after synthesis. In the presence of NH4Cl and in I-cell fibroblasts, the majority of newly synthesized alpha-galactosidase A was secreted as an Mr = 52,000 form. For comparison, the processing and stability of alpha-galactosidase A were examined in fibroblasts from five unrelated patients with Fabry disease, which is caused by deficient alpha-galactosidase A activity. In one cell line, synthesis of immunologically cross-reacting polypeptides was not detectable. In another, the synthesis, processing, and stability of alpha-galactosidase A was indistinguishable from that in normal fibroblasts. In a third Fabry cell line, the mutation retarded the maturation of alpha-galactosidase A. Finally, in two cell lines, alpha-galactosidase A polypeptides were synthesized that were rapidly degraded following delivery to lysosomes. These results clearly indicate that Fabry disease comprises a heterogeneous group of mutations affecting synthesis, processing, and stability of alpha-galactosidase A.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ammonium Chloride / pharmacology
  • Cell Line
  • Cross Reactions
  • Fabry Disease / enzymology*
  • Fabry Disease / genetics
  • Fibroblasts / enzymology*
  • Galactosidases / metabolism*
  • Hexosaminidases / metabolism
  • Humans
  • Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase
  • Molecular Weight
  • Mutation
  • alpha-Galactosidase / genetics
  • alpha-Galactosidase / metabolism*


  • Ammonium Chloride
  • Galactosidases
  • Hexosaminidases
  • alpha-Galactosidase
  • Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase