Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome)
Peining Lia, Amy B Bellowsa, Jerry N Thompsona b
a Laboratory of
Medical Genetics, University of Alabama at Birmingham, 420 Sparks
Center, 1720 7th Avenue South, Birmingham, AL 35294, USA, b Departments of Biochemistry and Molecular
Genetics, and Pediatrics, University of Alabama at Birmingham,
Birmingham, AL 35294, USA
Correspondence to: Dr Thompson.
Received 3 March 1998;
Revised version accepted for publication 17 June
1998
Mucopolysaccharidosis type II (Hunter syndrome) is an X linked
lysosomal storage disorder resulting from heterogeneous mutations in
the iduronate-2-sulphatase (IDS) gene. To detect IDS gene mutations, direct sequencing of IDS cDNA fragments coupled with assays on IDS
genomic amplicons was applied to 18 unrelated patients with MPS II.
Seventeen mutations were detected from the 18 patients including seven
missense mutations (S71R, A82E, A85T, R88C, R468W, R468Q, and E521V),
five deletions (
R95, 383delAT, 596delAACA, 1148delC, and 1216delCT),
two insertions (208insC and 1063insA), two splicing mutations
(1006+5g
c in intron 7, 1122CT in exon 8), and an intragenic
deletion of IDS exons 4, 5, 6, and 7. Nine of the small mutations were
novel mutations. Mutation 596delAACA was detected in two unrelated
patients. The mutation in intron 7 was found to cause aberrant splicing
and resulted in a 22 bp insertion into its mRNA transcript. The
intragenic deleted IDS gene expressed two aberrant mRNA transcripts
consisting of exons 1-2-8-9 and 3-8-9. Analysis of mutations A85T,
R88C, R468Q, R468W, and 438C/T found no polymorphism for the four
missense mutations but about 36% heterozygosity for the 438C/T silent
mutation. These results provide further evidence of mutational
heterogeneity for MPS II. Also, underlying sequence directed
mutagenesis mechanisms for some recurrent mutations in the IDS gene
were proposed.
Keywords: mucopolysaccharidosis type II; Hunter syndrome; iduronate-2-sulphatase gene; mutation detection
© 1999 by J Med Genet
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