Study on the severity and the primary prevention by carrier detection of MPS II (Hunter disease)

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Mucopolysaccharidosis II (Hunter disease), a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), has variable clinical phenotypes. Over 130 missense mutations were identified in the IDS gene from Hunter patients, but the correlation between genotype and phenotype has remained unclear.1) Sixteen missense mutations were characterized by stable expression analysis. Mutant proteins found in the severe phenotype had no activity and mutants found in the milder phenotype had a considerable residual activity (0.1 -2% of wild-type IDS activity).2) Sulfatases, including IDS, are members of a highly conserved gene family sharing an extensive sequence homology. Thus a tertiary structural model of IDS was constructed from the X-ray crystal structure of N-acetylgalactosamine-4-sulfatase, arylsulfatase and from a tertiary structural model of N-acetylgalactosamine-6-sulfatase, using homology modeling. The model structure of IDS had a monomeric form with two domains. The main structural feature of the larger domain was a beta-sheet with 10 strands sandwiched between alpha-helices. The smaller domain consisted of a four-stranded anti-paralled beta-sheet with an orthogonal alpha-helix.Based on the tertiary structural model, we will reveal effects of mutations on IDS structure and function.