title: 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.affiliation: Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario, Canada. alek.hinek@sickkids.on.ca.
authors.forename: A
authors.initials: A
authors.lastname: Hinek
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: J W
authors.initials: JW
authors.lastname: Callahan
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001704:Biopolymers / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics; D006224:Cricetinae; D020405:Dermis; D004547:Elastic Tissue / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D008970:Molecular Weight; D009085:Mucopolysaccharidosis IV / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012995:Solubility; D014333:Tropoelastin / Q000378:metabolism; D001616:beta-Galactosidase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D001704:Biopolymers; D018389:Codon, Nonsense; D014333:Tropoelastin; D004549:Elastin; D001616:beta-Galactosidase