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https://hdl.handle.net/2440/7539
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dc.contributor.author | Hein, L. | - |
dc.contributor.author | Bawden, M. | - |
dc.contributor.author | Muller, V. | - |
dc.contributor.author | Sillence, D. | - |
dc.contributor.author | Hopwood, J. | - |
dc.contributor.author | Brooks, D. | - |
dc.date.issued | 2004 | - |
dc.identifier.citation | Journal of Molecular Biology, 2004; 338(3):453-462 | - |
dc.identifier.issn | 0022-2836 | - |
dc.identifier.issn | 1089-8638 | - |
dc.identifier.uri | http://hdl.handle.net/2440/7539 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Leanne K Hein, Michael Bawden, Vivienne J Muller, David Sillence, John J Hopwood and Doug A Brooks | - |
dc.language.iso | en | - |
dc.publisher | Academic Press Ltd Elsevier Science Ltd | - |
dc.source.uri | http://dx.doi.org/10.1016/j.jmb.2004.03.012 | - |
dc.subject | α-l-iduronidase | - |
dc.subject | Hurler syndrome | - |
dc.subject | mucopolysaccharidosis type I | - |
dc.subject | stop codons | - |
dc.subject | read-through | - |
dc.title | a-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1016/j.jmb.2004.03.012 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Brooks, D. [0000-0001-9098-3626] | - |
Appears in Collections: | Aurora harvest 4 Paediatrics publications |
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