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.

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.

• Authors: A Hinek, S Zhang, A C Smith, J W Callahan
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 67 Issue 1 Pg. 23-36 (Jul 2000) ISSN: 0002-9297 [Print] United States
• PMID: 10841810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biopolymers
• Codon, Nonsense
• Tropoelastin
• Elastin
• beta-Galactosidase

Topics

• Alternative Splicing (genetics)
• Animals
• Biopolymers (metabolism)
• CHO Cells
• Cells, Cultured
• Codon, Nonsense (genetics)
• Cricetinae
• Dermis
• Elastic Tissue (enzymology, metabolism, pathology)
• Elastin (metabolism)
• Exons (genetics)
• Fibroblasts (enzymology, metabolism, pathology)
• Gangliosidosis, GM1 (enzymology, genetics, metabolism, pathology)
• Humans
• Infant
• Molecular Weight
• Mucopolysaccharidosis IV (enzymology, genetics, metabolism, pathology)
• Mutation (genetics)
• Protein Binding
• Solubility
• Tropoelastin (metabolism)
• beta-Galactosidase (chemistry, deficiency, genetics, metabolism)