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JIMD Reports - Case and Research Reports, Volume 13 pp 139–147Cite as

Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

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Part of the book series: JIMD Reports ((JIMD,volume 13))

Abstract

The premature stop codon mutations, Q70X and W402X, are the most common α-l-iduronidase gene (IDUA) mutations in mucopolysaccharidosis type I (MPS I) patients. Read-through drugs have been used to suppress premature stop codons, and this can potentially be used to treat patients who have this type of mutation. We examined the effects of aminoglycoside treatment on the IDUA mutations Q70X and W402X in cultured cells and show that 4,5-disubstituted aminoglycosides induced more read-through for the W402X mutation, while 4,6-disubstituted aminoglycosides promoted more read-through for the Q70X mutation: lividomycin (4,5-disubstituted) induced a 7.8-fold increase in α-l-iduronidase enzyme activity for the W402X mutation; NB54 (4,5-disubstituted) induced a 3.7 fold increase in the amount of α-l-iduronidase enzyme activity for the W402X mutation, but had less effect on the Q70X mutation, whereas gentamicin (4,6-disubstituted) had the reverse effect on read-through for both mutations. The predicted mRNA secondary structural changes for both mutations were markedly different, which may explain these different effects on read-through for these two premature stop codons.

Competing interests: None declared

Makoto Kamei and Karissa Kasperski are equal first authors.

This work was supported by an NHMRC project grant (NHMRC 511321; DAB and MF) and an NHMRC Senior Research Fellowship (DAB).

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    Authors and Affiliations

    1. Mechanisms in Cell Biology and Diseases Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, 5001, Australia

      Makoto Kamei, Karissa Kasperski, Emma J. Parkinson-Lawrence & Doug A. Brooks

    2. Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia, 5001, Australia

      Litsa Karageorgos & John J. Hopwood

    3. SA Pathology, North Adelaide, South Australia, 5006, Australia

      Maria Fuller

    4. Schulich Faculty of Chemistry, Technion, Israel Institute of Technology, Haifa, 32000, Israel

      Valery Belakhov & Timor Baasov

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    1. Makoto Kamei
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    Correspondence to Makoto Kamei .

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    Editors and Affiliations

    1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

      Johannes Zschocke

    2. Clinical Pharmacology Unit, WSU Division of Health Sciences, Spokane, USA

      K. Michael Gibson

    3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

      Garry Brown

    4. Department of Pediatrics IGMD, Tulane University Medical Center, New Orleans, Louisiana, USA

      Eva Morava

    5. Center for Child and Adolescent Medicine Heidelberg University Hospital, Heidelberg, Germany

      Verena Peters

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    Communicated by: Frits Wijburg, MD, PhD

    Synopsis

    Synopsis

    Examination of aminoglycoside-mediated read-through of premature stop codons present in the Q70X and the W402X mutations in the human α-iduronidase gene provided insights into the difference in efficacies seen in read-through drugs in use.

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    Kamei, M. et al. (2013). Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, Volume 13. JIMD Reports, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_270

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    • DOI: https://doi.org/10.1007/8904_2013_270

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