TY - JOUR
T1 - Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy
AU - Karageorgos, Litsa
AU - Brooks, Doug A.
AU - Harmatz, Paul
AU - Ketteridge, David
AU - Pollard, Anthony
AU - Melville, Elizabeth L.
AU - Parkinson-Lawrence, Emma
AU - Clements, Peter R.
AU - Hopwood, John J.
N1 - Funding Information:
We acknowledge funding support from the National Health and Medical Research Council of Australia and BioMarin Pharmaceutical, Inc. for this study. We thank co-investigators participating in the phase II MPS VI enzyme replacement therapy trial for their cooperation in providing fibroblasts for genotype analysis: J. Waterson (Children’s Hospital Oakland, USA); R. Steiner (Oregon Health & Science University, USA); R. Giugliani and I. Schwartz, (Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil); N. Guffon (Hôpital Edouard Herriot Pavillon S, Maladies Metaboliques, Lyon, France); M.C. Sá Miranda (Instituto de Biologia Molecular e Celular, Porto, Portugal); E-L Teles (Hospital de Sao João, Porto, Portugal); and L. Keppen (University of South Dakota, Sioux Falls, SD, USA). We are grateful to Chris Boulter and Kathy Nelson at the Women’s and Children’s Hospital in Adelaide, and Philip Cotter and Gloria Tung at CHRCO, for their assistance in culturing fibroblasts.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
KW - ARSB
KW - Arylsulfatase B
KW - MPS VI
KW - Maroteaux-Lamy syndrome
KW - Mucopolysaccharidosis type VI
KW - Mutational analysis
UR - http://www.scopus.com/inward/record.url?scp=33846252407&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2006.10.008
DO - 10.1016/j.ymgme.2006.10.008
M3 - Article
C2 - 17161971
AN - SCOPUS:33846252407
VL - 90
SP - 164
EP - 170
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2
ER -