Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/51915
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Type: Journal article
Title: Maroteaux-Lamy syndrome: Functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase B gene
Author: Garrido, E.
Cormand, B.
Hopwood, J.
Chabas, A.
Grinberg, D.
Vilageliu, L.
Citation: Molecular Genetics and Metabolism, 2008; 94(3):305-312
Publisher: Academic Press Inc Elsevier Science
Issue Date: 2008
ISSN: 1096-7192
1096-7206
Statement of
Responsibility: 
Elena Garrido, Bru Cormand, John J. Hopwood, Amparo Chabás, Daniel Grinberg and Lluïsa Vilageliu
Abstract: Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal disorder caused by deficiency of N-acetylgalactosamine-4-sulfatase (ARSB), which is required for the degradation of dermatan sulfate. We recently reported mutational screening of 12 Spanish and 4 Argentinian MPS VI patients. In the present study, seven missense mutations (c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.937C>G [p.P313A], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]) were transiently expressed in COS-7 cells and 4-sulfatase activity was measured in cell extracts. All mutations resulted in less than 6% of wild-type enzyme activity, in most cases undetectable. Mutations were expressed in their original haplotype context with respect to two non-synonymous polymorphisms present in the ARSB protein, p.V358M and p.S384N. The three less frequent haplotype combinations yielded an ARSB activity of 16%, 57% and 70%, when compared to the most frequent haplotype (p.358V and p.384S). Western blot analyses showed that the expressed mutations significantly reduced the amount of mature protein. Sub-cellular localization studies of mutant ARSB proteins in fibroblasts of MPS VI patients were performed. RNA analysis confirmed that nonsense-mediated RNA decay had taken place for all mutant alleles (c.1143-1G>C, c.1143-8T>G, p.W322X, c.427delG and c.1142+2T>A) which were candidates for causing RNA degradation by this mechanism. In summary, all the ARSB mutations studied had a significant effect on enzyme activity, protein processing and/or mRNA stability.
Keywords: Cells, Cultured; COS Cells; Animals; Cercopithecus aethiops; Humans; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Codon, Nonsense; Transfection; DNA Mutational Analysis; Protein Processing, Post-Translational; Enzyme Activation; RNA Stability; Mutation; Polymorphism, Single Nucleotide; Models, Molecular
RMID: 0020081070
DOI: 10.1016/j.ymgme.2008.02.012
Description (link): http://www.elsevier.com/wps/find/journaldescription.cws_home/622920/description#description
Appears in Collections:Paediatrics publications

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