Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome
Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome
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DOI：
10.1007/s10545-008-0876-z
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发表时间：
2008-12-01
影响因子：
4.2
通讯作者：
Svasti, J.
中科院分区：
文献类型：
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作者：
Keeratichamroen, S.;Cairns, J. R. Ketudat;Svasti, J.
编码酶艾杜糖醛酸-2-硫酸酯酶（IDS）的基因中的分子缺陷导致亨特氏病（粘多糖样变性II型，MPS II）。为了确定泰国MPS II的分子基础，对来自18个无关家族的20例Hunter综合征患者的IDS基因进行了分析。共鉴定出19种不同的突变，包括9种错义突变、3种无义突变、3种剪接位点改变、1种缺失、2种indel和1种重排，其中8种为新突变（p.R101C、p.D148V、p.G224A、p.K227E、p.E254X、p.W337X、c.440_442delinsTT和c.720_731delinsTTTCAGATGTTCTCCCCAG）。通过在COS 7细胞中表达具有单个突变的IDS，对在同一患者中鉴定的两种半合子变体p.R101C和p.R468Q的IDS活性进行评价，表明只有p.R468Q突变影响IDS蛋白活性。发现两个外显子突变c.257C>T（p.P86L）和c.418G>A激活多个隐蔽剪接位点，导致异常剪接的转录物。因此，泰国的MPS II是由影响IDS蛋白质产生和活性的多种缺陷引起的。
Molecular defects in the gene encoding the enzyme iduronate-2-sulfatase (IDS) result in Hunter disease (mucopolysaccharidosis type II, MPS II). To determine the molecular basis of MPS II in Thailand, the IDS gene was analysed in 20 Thai patients with Hunter syndrome from 18 unrelated families. A total of 19 different mutations, including 9 missense mutations, 3 nonsense mutations, 3 splice site alterations, 1 deletion, 2 indels, and 1 rearrangement were identified, 8 of which were novel (p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.W337X, c.440_442delinsTT and c.720_731delinsTTTCAGATGTTCTCCCCAG). Evaluation of the IDS activity of two hemizygous variants identified in the same patient, p.R101C and p.R468Q, by expression of IDS with the individual mutations in COS 7 cells indicated that only the p.R468Q mutation affected IDS protein activity. Two exonic mutations, c.257C>T (p.P86L) and c.418G>A, were found to activate multiple cryptic splice sites, resulting in aberrantly spliced transcripts. Thus, MPS II in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity.