Genotype-phenotype correlations in mucopolysaccharidosis type I using enzyme kinetics, immunoquantification and in vitro turnover studies

Susanna Bunge, Peter R. Clements, Sharon Byers, Wim J. Kleijer, Dough A. Brooks, John J. Hopwood

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Fibroblasts from 16 patients with known α-l-iduronidase gene mutations and different clinical phenotypes of mucopolysaccharidosis type I (MPS I) were investigated in order to establish genotype/phenotype correlations. Enzyme kinetic studies were performed using the specific α-l-iduronidase substrate iduronosyl anhydro[1-3H]mannitol-6-sulfate. Specific residual enzyme activities were estimated using the kinetic parameters and an immunoquantification assay which determines levels of α-l-iduronidase protein. Cells were cultured in the presence of [35S]sulfate and the in vivo degradation of accumulated labelled glycosaminoglycans measured after different chase times. Residual enzyme activity and different amounts of residual enzyme protein were present in extracts from 9 of 16 cell lines covering a wide spectrum of clinical severity. Catalytic capacity, calculated as the product of k(cat)/K(m) and ng iduronidase protein per mg cell protein, was shown in most cases to be directly related to the severity of clinical phenotype, with up to 7% of normal values for patients with the attenuated form of MPS I (Scheie) and less than 0.13% for severely affected patients (Hurler). In vitro turnover studies allowed further refinement of correlations between genotype and phenotype. Scheie disease compared to Hurler disease patients were shown to accumulate smaller amounts of glycosaminoglycans that were also turned over faster. A combination of turnover and residual enzyme data established a correlation between the genotype, the biochemical phenotype and the clinical course of this lysosomal storage disorder. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)249-256
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number3
Publication statusPublished - 30 Sep 1998


  • Enzyme kinetics
  • Genotype/phenotype correlation
  • Immunoquantification
  • Mucopolysaccharidosis type I

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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