Role of beta-galactosidase and elastin binding protein in lysosomal and nonlysosomal complexes of patients with GM1-gangliosidosis.
Anna Caciotti,Maria Alice Donati,Avihu Boneh,Alessandra d'Azzo,Antonio Federico,Rossella Parini,Danielas Antuzzi,T Bardelli,Daniele Nosi,Virginia Kimonis,Enrico Zammarchi,Amelia Morrone +11 more
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TLDR
The presence of genetic lesions in both GLB1 and EBP coding region does not directly predict impaired elastogenesis and that elastic fiber assembly has to be evaluated specifically in each case, Nevertheless, the degree of EBP involvement may be linked to specific clinical findings.Abstract:
GM1-gangliosidosis is a lysosomal storage disorder caused by a deficiency of β-galactosidase (GLB1). The GLB1 gene gives rise to the GLB1 lysosomal enzyme and to the elastin binding protein (EBP), involved in elastic fiber deposition. GLB1 forms a complex with protective protein cathepsin A (PPCA), alpha neuraminidase (NEU1), and galactosamine 6-sulphate sulfatase (GALNS) inside lysosomes, while EBP binds to PPCA and NEU1 on the cell surface. We investigated the function of the GLB1 and EBP mutated proteins by analyzing the clinical, genetic, and cellular data of 11 GM1-gangliosidosis patients. Their molecular analysis, followed by expression studies, lead to the identification of four new and 10 known GLB1 mutations. Some common amino acid substitutions [c.1445G>A (p.Arg482H), c.622C>T (p.Arg208His), c.175C>T (p.Arg59Cys) and c.176G>A (p.Arg59His)] were present in the GLB1 enzyme of several patients, all of Mediterranean origin, suggesting a common origin. Western blotting analyses against GLB1, EBP, and PPCA proteins showed that the identified mutations affect GLB1 enzyme activity and/or stability. The c.1445G>A (p.Arg482His), c.175C>T (p.Arg59Cys), c.733+2T>C, c.1736G>A (p.Gly579Asp), and c.1051C>T (p.Arg351X) GLB1 mutations, affect the stabilization of PPCA probably because they hamper the interaction between GLB1/EBP and PPCA within the multiprotein complex. The amount of EBP was normal, but the detection of impaired elastogenesis in such patients suggests an alteration in its function. We conclude that the presence of genetic lesions in both GLB1 and EBP coding region does not directly predict impaired elastogenesis and that elastic fiber assembly has to be evaluated specifically in each case. Nevertheless, the degree of EBP involvement may be linked to specific clinical findings. Hum Mutat 25:285–292, 2005. © 2005 Wiley-Liss, Inc.read more
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Senescence‐associated β‐galactosidase is lysosomal β‐galactosidase
Bo Yun Lee,Jung A. Han,Jun Sub Im,Amelia Morrone,Kimberly L. Johung,Edward C. Goodwin,Wim J. Kleijer,Daniel DiMaio,Eun Seong Hwang,Eun Seong Hwang +9 more
TL;DR: It is demonstrated here that SA‐β‐gal activity is expressed from GLB1, the gene encoding lysosomal β‐D‐galactosidase, the activity of which is typically measured at acidic pH 4.5.
Journal ArticleDOI
GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects.
TL;DR: An overview of the clinical and molecular findings in patients with GM(1) gangliosidosis is given and therapeutic approaches which are currently under investigation in animal models of the disease are described.
Journal ArticleDOI
Lysosomal sialidase (neuraminidase-1) is targeted to the cell surface in a multiprotein complex that facilitates elastic fiber assembly.
TL;DR: Hinek et al. as mentioned in this paper showed that the 67-kDa elastin-binding protein (EBP) also forms a cell surface-targeted molecular complex with protective protein/cathepsin A and sialidase (neuraminidase-1).
Journal ArticleDOI
Sustained Normalization of Neurological Disease After Intracranial Gene Therapy in a Feline Model
Victoria J. McCurdy,Aime K. Johnson,Heather L. Gray-Edwards,Ashley N. Randle,Brandon L. Brunson,Nancy E. Morrison,Nouha Salibi,Nouha Salibi,Jacob A. Johnson,Misako Hwang,Ronald J. Beyers,Stanley G. LeRoy,Stacy Maitland,Thomas S. Denney,Nancy R. Cox,Henry J. Baker,Miguel Sena-Esteves,Douglas R. Martin +17 more
TL;DR: Sustained correction of the GM1 gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
Journal ArticleDOI
Morquio A Syndrome-Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus-Specific Database
Amelia Morrone,Anna Caciotti,Robert Atwood,K. Davidson,Chaoyi Du,Patricia Francis-Lyon,Paul Harmatz,Matthew Mealiffe,Sean D. Mooney,Tal Ronnen Oron,April B. Ryles,Karl A Zawadzki,Nicole Miller +12 more
TL;DR: A locus‐specific database for the GAL NS gene is created that catalogs all reported alterations in GALNS to date and highlights the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALns alterations.
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