Glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid α-glucosidase (AαGlu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant AαGlu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the AαGlu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AαGlu in a dose dependent manner, while it had no effect on the reference enzyme β-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant AαGlu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AαGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10 μmol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AαGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII.

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Molecular Genetics and Metabolism
Erasmus MC: University Medical Center Rotterdam

Okumiya, T., Kroos, M., Vliet, L. V., Takeuchi, H., van der Ploeg, A., & Reuser, A. (2007). Chemical chaperones improve transport and enhance stability of mutant α-glucosidases in glycogen storage disease type II. Molecular Genetics and Metabolism, 90(1), 49–57. doi:10.1016/j.ymgme.2006.09.010