1. Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of beta-galactosidase.
- Author
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Hinek A, Zhang S, Smith AC, and Callahan JW
- Subjects
- Animals, Biopolymers metabolism, CHO Cells, Cells, Cultured, Codon, Nonsense genetics, Cricetinae, Dermis, Elastic Tissue enzymology, Elastic Tissue pathology, Elastin metabolism, Exons genetics, Fibroblasts enzymology, Fibroblasts metabolism, Fibroblasts pathology, Gangliosidosis, GM1 enzymology, Gangliosidosis, GM1 genetics, Gangliosidosis, GM1 pathology, Humans, Infant, Molecular Weight, Mucopolysaccharidosis IV enzymology, Mucopolysaccharidosis IV genetics, Mucopolysaccharidosis IV pathology, Mutation genetics, Protein Binding, Solubility, Tropoelastin metabolism, beta-Galactosidase chemistry, beta-Galactosidase metabolism, Alternative Splicing genetics, Elastic Tissue metabolism, Gangliosidosis, GM1 metabolism, Mucopolysaccharidosis IV metabolism, beta-Galactosidase deficiency, beta-Galactosidase genetics
- Abstract
We have previously shown that intracellular trafficking and extracellular assembly of tropoelastin into elastic fibers is facilitated by the 67-kD elastin-binding protein identical to an enzymatically inactive, alternatively spliced variant of beta-galactosidase (S-Gal). In the present study, we investigated elastic-fiber assembly in cultures of dermal fibroblasts from patients with either Morquio B disease or GM1-gangliosidosis who bore different mutations of the beta-galactosidase gene. We found that fibroblasts taken from patients with an adult form of GM1-gangliosidosis and from patients with an infantile form, carrying a missense mutations in the beta-galactosidase gene-mutations that caused deficiency in lysosomal beta-galactosidase but not in S-Gal-assembled normal elastic fibers. In contrast, fibroblasts from two cases of infantile GM1-gangliosidosis that bear nonsense mutations of the beta-galactosidase gene, as well as fibroblasts from four patients with Morquio B who had mutations causing deficiency in both forms of beta-galactosidase, did not assemble elastic fibers. We also demonstrated that S-Gal-deficient fibroblasts from patients with either GM1-gangliosidosis or Morquio B can acquire the S-Gal protein, produced by coculturing of Chinese hamster ovary cells permanently transected with S-Gal cDNA, resulting in improved deposition of elastic fibers. The present study provides a novel and natural model validating functional roles of S-Gal in elastogenesis and elucidates an association between impaired elastogenesis and the development of connective-tissue disorders in patients with Morquio B disease and in patients with an infantile form of GM1-gangliosidosis.
- Published
- 2000
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