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The pharmacological chaperone 1‐deoxygalactonojirimycin increases α‐galactosidase A levels in Fabry patient cell lines
Author(s) -
Benjamin E. R.,
Flanagan J. J.,
Schilling A.,
Chang H. H.,
Agarwal L.,
Katz E.,
Wu X.,
Pine C.,
Wustman B.,
Desnick R. J.,
Lockhart D. J.,
Valenzano K. J.
Publication year - 2009
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-009-1077-0
Subject(s) - fabry disease , globotriaosylceramide , missense mutation , alpha galactosidase , mutant , biology , microbiology and biotechnology , mutation , incubation , biochemistry , gene , medicine , disease
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 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 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.