Journal of Inherited Metabolic Disease

, Volume 32, Issue 3, pp 424–440

The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines

  • E. R. Benjamin
  • J. J. Flanagan
  • A. Schilling
  • H. H. Chang
  • L. Agarwal
  • E. Katz
  • X. Wu
  • C. Pine
  • B. Wustman
  • R. J. Desnick
  • D. J. Lockhart
  • K. J. Valenzano
Original Article

DOI: 10.1007/s10545-009-1077-0

Cite this article as:
Benjamin, E.R., Flanagan, J.J., Schilling, A. et al. J Inherit Metab Dis (2009) 32: 424. doi:10.1007/s10545-009-1077-0

Summary

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (α-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 α-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of α-Gal A, the effect of DGJ incubation on α-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 α-Gal A levels ranged from 0 to 52% of normal. Increases in α-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 EC50 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 α-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.

Abbreviations

DGJ

1-deoxygalactonojirimycin hydrochloride (AT1001: migalastat hydrochloride)

EC50

effective concentration 50% (the concentration of DGJ yielding 50% of the maximal effect)

GalNac

N-acetyl-d-galactosamine

GL-3

globotriaosylceramide

GLA

gene encoding α-Gal A

α-Gal A

α-galactosidase A

4-MU

4-methylumbelliferone

4-MUG

4-MU-α-d-galactopyranoside

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • E. R. Benjamin
    • 1
  • J. J. Flanagan
    • 1
  • A. Schilling
    • 1
  • H. H. Chang
    • 1
  • L. Agarwal
    • 1
  • E. Katz
    • 1
  • X. Wu
    • 1
  • C. Pine
    • 1
  • B. Wustman
    • 1
  • R. J. Desnick
    • 2
  • D. J. Lockhart
    • 1
  • K. J. Valenzano
    • 1
  1. 1.Amicus TherapeuticsCranburyUSA
  2. 2.Department of Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA