Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/7539
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Type: Journal article
Title: a-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients
Author: Hein, L.
Bawden, M.
Muller, V.
Sillence, D.
Hopwood, J.
Brooks, D.
Citation: Journal of Molecular Biology, 2004; 338(3):453-462
Publisher: Academic Press Ltd Elsevier Science Ltd
Issue Date: 2004
ISSN: 0022-2836
1089-8638
Statement of
Responsibility: 
Leanne K Hein, Michael Bawden, Vivienne J Muller, David Sillence, John J Hopwood and Doug A Brooks
Abstract: α-l-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in α-l-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the lysosomal storage disorder mucopolysaccharidosis type I (MPS I; Hurler and Scheie syndromes; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common α-l-iduronidase gene (IDUA) mutations accounting for up to 70% of MPS I disease alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature IDUA stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an MPS I patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical Hurler syndrome (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in MPS I patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of MPS I patients.
Keywords: α-l-iduronidase
Hurler syndrome
mucopolysaccharidosis type I
stop codons
read-through
DOI: 10.1016/j.jmb.2004.03.012
Published version: http://dx.doi.org/10.1016/j.jmb.2004.03.012
Appears in Collections:Aurora harvest 4
Paediatrics publications

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