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(American Journal of Pathology. 2005;167:1689-1698.)
© 2005 American Society for Investigative Pathology

Primary and Secondary Elastin-Binding Protein Defect Leads to Impaired Elastogenesis in Fibroblasts from G_M1-Gangliosidosis Patients

Anna Caciotti^*, Maria Alice Donati^*, Tiziana Bardelli^*, Alessandra d’Azzo, Graziella Massai^*, Luciana Luciani, Enrico Zammarchi^* and Amelia Morrone^*

From the Department of Pediatrics,^* Meyer Hospital, Florence, Italy; the Pediatric Unit, Melegnano Hospital, Milan, Italy; and the Department of Genetics, St. Jude Children’s Research Hospital, Memphis, Tennessee

G_M1-gangliosidosis is a lysosomal storage disorder caused by acid ß-galactosidase deficiency. Aside from the lysosomal ß-galactosidase enzyme, the ß-galactosidase gene also encodes the elastin-binding protein (EBP), deficiency in which impairs elastogenesis. Using expression studies and Western blots of COS-1 cells, we identified and characterized four new and two known ß-galactosidase gene mutations detected in G_M1-gangliosidosis patients with infantile, juvenile, or adult forms of disease. We then focused on impaired elastogenesis detected in fibroblasts from patients with infantile and juvenile disease. The juvenile patient showed connective-tissue abnormalities, unusual urinary keratan sulfate excretion, and an EBP reduction, despite mutations affecting only ß-galactosidase. Because galactosugar-bearing moieties may alter EBP function and impair elastogenesis, we assessed infantile and juvenile patients for the source of altered elastogenesis. We confirmed that the infantile patient’s impaired elastogenesis arose from a primary EBP defect, according to molecular analysis. We examined the juvenile’s fibroblasts by immunohistochemistry, addition of keratanase, soluble/insoluble elastin assay, and radiolabeling of tropoelastin. These experiments revealed that the juvenile’s impaired elastogenesis likely arose from secondary EBP deficiency caused by keratan sulfate accumulation. Thus, impaired elastogenesis in G_M1-gangliosidosis can arise from primary or secondary EBP defects in fibroblasts from infantile and juvenile patients, respectively.

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