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Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: Enzymatic activity, protein processing and structural analysis

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Summary

Mucopolysaccharidosis II (Hunter disease), a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), has variable clinical phenotypes. Nearly 300 different mutations have been identified in the IDS gene from patients with Hunter disease, but the correlation between the genotype and phenotype has remained unclear. We studied the characteristics of 11 missense mutations, which were detected in the patients or artificially introduced, using stable expression experiments and structural analysis. The mutants found in the attenuated phenotype showed considerable residual activity (0.2–2.4% of the wild-type IDS activity) and those in the severe phenotype had no activity. In immunoblot analysis, both the 73–75 kDa precursor and processed forms were detected in the expression of `attenuated' mutants (R48P, A85T and W337R) and the artificial active site mutants (C84S, C84T). The 73–75 kDa initial precursor was detected in the 'severe' mutants (P86L, S333L, S349I, R468Q, R468L). The truncated 68 kDa precursor form was synthesized in the Q531X mutant. The results of immunoblotting indicated rapid degradation and/or insufficiency in processing as a result of structural alteration of the IDS protein. A combination of analyses of genotype and molecular phenotypes, including enzyme activity, protein processing and structural analysis with an engineered reference protein, could provide an avenue to understanding the molecular mechanism of the disease and could give a useful tool for the evaluation of possible therapeutic chemical compounds.

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Abbreviations

IDS:

iduronate-2-sulfatase

4S:

arylsulfatase B (N-acetylgalactosamine-4S sulfatase)

ASA:

arylsulfatase A

GALNS:

N-acetylgalactosamine-6S sulfatase

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Authors and Affiliations

  1. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan

    K. Sukegawa-Hayasaka, Z. Kato, S. Tomatsu, T. Fukao & N. Kondo

  2. Division of Virology, Center for Emerging Infectious Diseases (CEID), Gifu University, Gifu, Japan

    Z. Kato & N. Kondo

  3. Center for Advanced Drug Research (CADR), Gifu University, Gifu, Japan

    Z. Kato & N. Kondo

  4. Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA

    Z. Kato

  5. Research Center for Structural Biology, Institute for Protein Research, Osaka University, Osaka, Japan

    H. Nakamura

  6. Department of Pediatrics, St. Louis University, Pediatric Research Institute, St. Louis, Missouri, USA

    S. Tomatsu

  7. Division of Prion Research, Center for Emerging Infectious Diseases (CEID), Gifu University, Gifu, Japan

    K. Kuwata

  8. Department of Human Welfare, Faculty of Human Welfare, Chubu Gakuin University, Gifu, Japan

    T. Orii

Authors
  1. K. Sukegawa-Hayasaka
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  2. Z. Kato
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  3. H. Nakamura
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  4. S. Tomatsu
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  5. T. Fukao
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  6. K. Kuwata
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  7. T. Orii
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  8. N. Kondo
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Corresponding author

Correspondence to K. Sukegawa-Hayasaka.

Additional information

Communicating editor: Ed Wraith

Competing interests: None declared

References to electronic databases: Iduronate-2-sulfatase EC3.1.6.13; mucopolysaccharidoisis II (Hunter disease) OMIM 309900

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Sukegawa-Hayasaka, K., Kato, Z., Nakamura, H. et al. Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: Enzymatic activity, protein processing and structural analysis. J Inherit Metab Dis 29, 755–761 (2006). https://doi.org/10.1007/s10545-006-0440-7

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  • DOI: https://doi.org/10.1007/s10545-006-0440-7

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