Hurler syndrome is the most severe form of a lysosomal storage disease caused by loss of the enzyme α-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 amino-glycoside 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 α-L-iduronidase activity when cultured in the presence of gentamicin, resulting in the restoration of 2.8% of normal α-L-iduronidase activity. Determination of α-L-iduronidase protein levels by an immunoquantification assay indicated that gentamicin treatment produced a similar increase in α-L-iduronidase protein in Hurler cells. Both the α-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.
|Number of pages||9|
|Journal||Human Molecular Genetics|
|Publication status||Published or Issued - 1 Feb 2001|
ASJC Scopus subject areas
- Molecular Biology