Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/7344
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Type: Journal article
Title: Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of a-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation
Author: Keeling, K.
Brooks, D.
Hopwood, J.
Li, P.
Thompson, J.
Bedwell, D.
Citation: Human Molecular Genetics, 2001; 10(3):291-299
Publisher: Oxford Univ Press
Issue Date: 2001
ISSN: 0964-6906
1460-2083
Statement of
Responsibility: 
Kim M. Keeling, Doug A. Brooks, John J. Hopwood, Peining Li, Jerry N. Thompson and David M. Bedwell
Abstract: Hurler syndrome is the most severe form of a lysosomal storage disease caused by loss of the enzyme alpha-L-iduronidase (encoded by the IDUA gene), which participates in the degradation of glycosaminoglycans (GAGs) within the lysosome. In some populations, premature stop mutations represent roughly two-thirds of the mutations that cause Hurler syndrome. In this study we investigated whether the aminoglycoside gentamicin can suppress stop mutations within the IDUA gene. We found that a Hurler syndrome fibroblast cell line heterozygous for the IDUA stop mutations Q70X and W402X showed a significant increase in alpha-L-iduronidase activity when cultured in the presence of gentamicin, resulting in the restoration of 2.8% of normal alpha-L-iduronidase activity. Determination of alpha-L-iduronidase protein levels by an immunoquantification assay indicated that gentamicin treatment produced a similar increase in alpha-L-iduronidase protein in Hurler cells. Both the alpha-L-iduronidase activity and protein level resulting from this treatment have previously been correlated with mild Hurler phenotypes. Although Hurler fibroblasts contain a much higher level of GAGs than normal, we found that gentamicin treatment reduced GAG accumulation in Hurler cells to a normal level. We also found that a reduced GAG level could be sustained for at least 2 days after gentamicin treatment was discontinued. The reduction in the GAG level was also reflected in a marked reduction in lysosomal vacuolation. Taken together, these results suggest that the suppression of premature stop mutations may provide an effective treatment for Hurler syndrome patients with premature stop mutations in the IDUA gene.
Keywords: Cell Line; Lysosomes; Fibroblasts; Humans; Mucopolysaccharidosis I; Iduronidase; Gentamicins; Glycosaminoglycans; Codon, Terminator; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Mutation; HSP70 Heat-Shock Proteins
Description: Copyright © 2001 Oxford University Press
RMID: 0020010913
DOI: 10.1093/hmg/10.3.291
Appears in Collections:Paediatrics publications

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