The Pharmacological Chaperone 1-deoxygalactonojirimycin Increases Alpha-Galactosidase A Levels in Fabry Patient Cell Lines

J Inherit Metab Dis. 2009 Jun;32(3):424-40. doi: 10.1007/s10545-009-1077-0. Epub 2009 Apr 18.

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding alpha-galactosidase A (alpha-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds alpha-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of alpha-Gal A, the effect of DGJ incubation on alpha-Gal A levels was assessed in cultured lymphoblasts from males with Fabry disease representing 75 different missense mutations, one insertion, and one splice-site mutation. Baseline alpha-Gal A levels ranged from 0 to 52% of normal. Increases in alpha-Gal A levels (1.5- to 28-fold) after continuous DGJ incubation for 5 days were seen for 49 different missense mutant forms with varying EC(50) values (820 nmol/L to >1 mmol/L). Amino acid substitutions in responsive forms were located throughout both structural domains of the enzyme. Half of the missense mutant forms associated with classic (early-onset) Fabry disease and a majority (90%) associated with later-onset Fabry disease were responsive. In cultured fibroblasts from males with Fabry disease, the responses to DGJ were comparable to those of lymphoblasts with the same mutation. Importantly, elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant alpha-Gal A levels can reduce accumulated substrate. These data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations.

Publication types

  • Comparative Study

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Cell Line
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Fabry Disease / enzymology
  • Fabry Disease / metabolism
  • Fabry Disease / pathology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Half-Life
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Male
  • Models, Molecular
  • Molecular Chaperones / pharmacology
  • Mutation, Missense / physiology
  • Up-Regulation / drug effects
  • alpha-Galactosidase / chemistry
  • alpha-Galactosidase / genetics
  • alpha-Galactosidase / metabolism*

Substances

  • Molecular Chaperones
  • 1-Deoxynojirimycin
  • migalastat
  • alpha-Galactosidase

Associated data

  • OMIM/310500