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|Title:||Maroteaux-Lamy syndrome: Functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase B gene|
|Citation:||Molecular Genetics and Metabolism, 2008; 94(3):305-312|
|Publisher:||Academic Press Inc Elsevier Science|
|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|
|Appears in Collections:||Paediatrics publications|
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