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

粘多糖样沉积症II（亨特氏病），一种由艾杜糖醛酸-2-硫酸酯酶（IDS）缺乏引起的溶酶体储存疾病，具有不同的临床表型。在Hunter患者的IDS基因中鉴定出超过130个错义突变，但基因型与表型之间的相关性仍不清楚。1）通过稳定表达分析表征了16个错义突变。在严重表型中发现的突变蛋白没有活性，而在较温和表型中发现的突变体具有相当大的残余活性（野生型IDS活性的0.1 - 2%）。2）硫酸酯酶，包括IDS，是共享广泛序列同源性的高度保守基因家族的成员。因此，IDS的三级结构模型是从N-乙酰半乳糖胺-4-硫酸酯酶，芳基硫酸酯酶的X-射线晶体结构和N-乙酰半乳糖胺-6-硫酸酯酶的三级结构模型，使用同源建模。入侵检测系统的模型结构是一个具有两个域的单体形式。较大结构域的主要结构特征是β-折叠，其中10条链夹在α-螺旋之间。小的结构域由一个四链的反平行β折叠和一个正交的α螺旋组成。基于三级结构模型，我们将揭示突变对IDS结构和功能的影响。

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.