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Impaired elastogenesis in Hurler disease: dermatan sulfate accumulation linked to deficiency in elastin-binding
1Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario, Canada. alek.hinek@sickkids.on.ca
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.
Abstract:
Hurler disease resulting from a deficiency in alpha-L-iduronidase, which causes an accumulation of dermatan sulfate and heparan sulfate glycosaminoglycans, is characterized by connective tissue and skeletal deformations, cardiomyopathy, cardiac valve defects, and progressive coronary artery stenosis. In this report, we present evidence that accumulation of dermatan sulfate but not heparan sulfate moieties is linked to impaired elastic fiber assembly that, in turn, contributes substantially to the development of the clinical phenotype in Hurler disease. Our data suggest that dermatan sulfate-bearing moieties bind to and cause functional inactivation of the 67-kd elastin-binding protein, a molecular chaperone for tropoelastin, which normally facilitates its secretion and assembly into elastic fibers. We demonstrate that, in contrast to normal skin fibroblasts and cells from Sanfilippo disease, which accumulate heparan sulfate, Hurler fibroblasts show reduced expression of elastin-binding protein and do not assemble elastic fibers, despite an adequate synthesis of tropoelastin and sufficient production of a microfibrillar scaffold of elastic fibers. Because cultured Hurler fibroblasts proliferate more quickly than their normal counterparts and the addition of exogenous insoluble elastin reduces their proliferation, we suggest that cell contacts with insoluble elastin play an important role in controlling their proliferation.