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The pharmacological chaperone N-n-butyl-deoxygalactonojirimycin enhances β-galactosidase processing and activity in fibroblasts of a patient with infantile GM1-gangliosidosis


GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization. Deoxygalactonojirimycin (DGJ) and its derivatives are pharmaceutical chaperones that directly bind to mutated β-Gal in the ER promoting its folding and trafficking to lysosomes and thus enhancing its activity. An Emirati child has been diagnosed with infantile GM1-gangliosidosis carrying the reported p.D151Y variant. We show that p.D151Y β-Gal in patient’s fibroblasts retained < 1% residual activity due to impaired processing and trafficking. The amino acid substitution significantly affected the enzyme conformation; however, p.D151Y β-Gal was amenable for partial rescue in the presence of glycerol or at reduced temperature where activity was enhanced with ~ 2.3 and 7 folds, respectively. The butyl (NB-DGJ) and nonyl (NN-DGJ) derivatives of DGJ chaperoning function were evaluated by measuring their IC50s and ability to stabilize the wild-type β-Gal against thermal degradation. Although NN-DGJ showed higher affinity to β-Gal, it did not show a significant enhancement in p.D151Y β-Gal activity. However, NB-DGJ promoted p.D151Y β-Gal maturation and enhanced its activity up to ~ 4.5% of control activity within 24 h which was significantly increased to ~ 10% within 6 days. NB-DGJ enhancement effect was sustained over 3 days after washing it out from culture media. We therefore conclude that NB-DGJ might be a promising therapeutic chemical chaperone in infantile GM1 amenable variants and therefore warrants further analysis for its clinical applications.

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We are indebted to the family for their participation in this study. This study was supported by research grants from the United Arab Emirates University (Grants 31R134 and 31M369) and a PhD studentship for FEM (31M289).

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All authors contributed to the study conception and design. FEM and BRA designed the experimental plan. Material preparation and molecular analysis were performed by FEM. MAS and MAG performed the molecular modelling analysis. FAJ handled the patient and performed the clinical evaluation. The first draft of the manuscript was written by FEM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bassam R. Ali.

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All authors have declared that no competing interests exist.

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All procedures performed in the study involving human participants were in accordance with Al-Ain Medical Human Research Ethics Committee (AMHREC) according to the national regulations (Approval numbers 10/09 and ERH-2015-3241 15-115) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Samples were collected from the patient after obtaining written informed consents from the parents.

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Mohamed, F.E., Al Sorkhy, M., Ghattas, M.A. et al. The pharmacological chaperone N-n-butyl-deoxygalactonojirimycin enhances β-galactosidase processing and activity in fibroblasts of a patient with infantile GM1-gangliosidosis. Hum Genet 139, 657–673 (2020).

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