Karageorgos L, Harmatz P, Simon J, Pollard A, Clements PR, Brooks DA,
Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial
of enzyme replacement therapy.
Hum Mutat. 2004 Mar;23(3):229-33. doi: 10.1002/humu.10313.
Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a
lysosomal storage disorder caused by a deficiency of
N-acetylgalactosamine-4-sulfatase (ARSB). Seven MPS VI patients were chosen for
the initial clinical trial 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.
Nine substitutions (c.289C>T [p.Q97X], c.629A>G [p.Y210C], c.707T>C [p.L236P],
c.936G>T [p.W312C], c.944G>A [p.R315Q], c.962T>C [p.L321P], c.979C>T [p.R327X],
c.1151G>A [p.S384N], and c.1450A>G [p.R484G]), two deletions (c.356_358delTAC
[p.Y86del] and c.427delG), and one intronic mutation (c.1336+2T>G) were
identified. A total of 7 out of the 12 mutations identified were novel (p.Y86del,
p.Q97X, p.W312C, p.R327X, c.427delG, p.R484G, and c.1336+2T>G). Two of these
novel mutations (p.Y86del and p.W312C) were expressed in Chinese hamster ovary
cells and analyzed for residual ARSB activity and mutant ARSB protein. The two
common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified
among the patients, along with the silent mutation c.1191A>G. Cultured fibroblast
ARSB mutant protein and residual activity were determined for each patient, and,
together with genotype information, were used to predict the expected clinical
severity of each MPS VI patient.
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