A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease

Hum Mutat. 2011 Aug;32(8):965-77. doi: 10.1002/humu.21530. Epub 2011 Jul 12.


Fabry disease is caused by mutations in the gene (GLA) that encodes α-galactosidase A (α-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes α-Gal A, increasing total cellular levels and activity for some mutant forms (defined as "responsive"). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of α-Gal A that are responsive to AT1001. Concentration-dependent increases in α-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of α-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 α-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 µM) were generally consistent with observed increases in α-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of α-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms.

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / metabolism
  • 1-Deoxynojirimycin / pharmacology
  • Biological Assay
  • Enzyme Activation / drug effects
  • Fabry Disease / genetics*
  • Fabry Disease / metabolism
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Mutant Proteins / analysis*
  • Mutant Proteins / metabolism
  • Point Mutation / genetics
  • Protein Conformation
  • alpha-Galactosidase / chemistry
  • alpha-Galactosidase / genetics*
  • alpha-Galactosidase / metabolism


  • Mutant Proteins
  • 1-Deoxynojirimycin
  • migalastat
  • alpha-Galactosidase