Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy

Mucopolysaccharidosis type VI (MPS VI; Maroteaux–Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (ARSB) gene. These mutations result in a deficiency of ARSB activity. Ten MPS VI patients were involved in a phase II clinical study of enzyme...

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Bibliographic Details
Published in:Molecular genetics and metabolism 2007-02, Vol.90 (2), p.164-170
Main Authors: Karageorgos, Litsa, Brooks, Doug A., Harmatz, Paul, Ketteridge, David, Pollard, Anthony, Melville, Elizabeth L., Parkinson-Lawrence, Emma, Clements, Peter R., Hopwood, John J.
Format: Article
Language:English
Subjects:
Adolescent
Adult
ARSB
Arylsulfatase B
Child
DNA Mutational Analysis
Female
Humans
Male
Maroteaux–Lamy syndrome
MPS VI
Mucopolysaccharidosis IV - drug therapy
Mucopolysaccharidosis IV - genetics
Mucopolysaccharidosis type VI
Mutation
Mutational analysis
N-Acetylgalactosamine-4-Sulfatase - genetics
N-Acetylgalactosamine-4-Sulfatase - therapeutic use
Recombinant Proteins - genetics
Recombinant Proteins - therapeutic use
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Summary:Mucopolysaccharidosis type VI (MPS VI; Maroteaux–Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (ARSB) gene. These mutations result in a deficiency of ARSB activity. Ten MPS VI patients were involved in a phase II clinical study of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Thirteen substitutions (c.215T>G [p.L72R] c.284G>A [p.R95Q], c.305G>A [p.R102H], c.323G>T [p.G108V], c.389C>T [p.P130L], c.511G>A [p.G171S], c.904G>A [p.G302R], c.944G>A [p.R315Q], c.1057T>C [p.W353R], c.1151G>A [p.S384N], c.1178A>C [p.H393P], c.1289A>G [p.H430R] and c.1336G>C [p.G446R]), one deletion (c.238delG), and two intronic mutations (c.1213+5G>A and c.1214-2A>G) were identified. Nine of the 16 mutations identified were novel (R102H, G108V, P130L, G171S, W353R, H430R, G446R, c.1213+5G>A and c.1214-2A>G). The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified in some of the patients, along with the silent mutations c.972A>G and c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient and, together with genotype information, used to predict the expected clinical severity of each patient.
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2006.10.008