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Impaired elastogenesis in Hurler disease: dermatan sulfate accumulation linked to deficiency in elastin-binding

A Hinek1, S E Wilson

  • 1Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario, Canada. alek.hinek@sickkids.on.ca

The American Journal of Pathology
|March 7, 2000
PubMed

Insights

Accumulation of dermatan sulfate in Hurler disease impairs elastic fiber assembly by inactivating elastin-binding protein. This finding offers new insights into the disease

Area of Science:

  • Biochemistry
  • Genetics
  • Cell Biology

Background:

  • Hurler disease, caused by alpha-L-iduronidase deficiency, leads to glycosaminoglycan accumulation and severe clinical manifestations.
  • Key features include connective tissue and skeletal issues, cardiomyopathy, and cardiac valve defects.

Purpose of the Study:

  • To investigate the specific role of glycosaminoglycan accumulation in the pathogenesis of Hurler disease.
  • To elucidate the mechanism by which dermatan sulfate accumulation affects elastic fiber formation and cellular function.

Main Methods:

  • Analysis of glycosaminoglycan accumulation in Hurler fibroblasts.
  • Assessment of elastic fiber assembly and tropoelastin secretion.
  • Evaluation of elastin-binding protein expression and function.
  • Cell proliferation assays with and without exogenous elastin.

Main Results:

  • Dermatan sulfate accumulation, not heparan sulfate, is linked to impaired elastic fiber assembly in Hurler disease.
  • Dermatan sulfate moieties inactivate the 67-kd elastin-binding protein, a key chaperone for tropoelastin.
  • Hurler fibroblasts exhibit reduced elastin-binding protein expression and defective elastic fiber formation.
  • Hurler fibroblasts show increased proliferation, which is reduced by exogenous insoluble elastin.

Conclusions:

  • Dermatan sulfate accumulation and subsequent elastin-binding protein inactivation are critical contributors to the Hurler disease phenotype.
  • Defective elastic fiber assembly significantly impacts disease development.
  • Cellular interactions with elastin may regulate fibroblast proliferation, suggesting a potential therapeutic target.

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