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...Continue Reading
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