Prevalence of Werner's syndrome heterozygotes in Japan
Prevalence of Werner's syndrome heterozygotes in Japan
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DOI：
10.1016/s0140-6736(98)05869-3
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发表时间：
1999-05-22
期刊：
影响因子：
168.9
通讯作者：
Furuichi, Y
中科院分区：
文献类型：
--
作者：
Satoh, M;Imai, M;Furuichi, Y
沃纳综合征是一种常染色体隐性遗传疾病，导致过早衰老，伴随着对癌症的易感性增加。致病基因（WRN）编码DNA解旋酶。[1]从1904年到1996年，全世界共报告了1200例患者; 845例来自日本。患者分布在日本各地。[2]但是突变的WRN基因在普通人群中的分布有多广呢？我们分析了63例Werner综合征患者的突变，发现在126条染色体中，65条（51.6%）染色体有突变4，22条（17.5%）染色体有突变6，3，其余染色体有其他突变。我们专注于突变4和6。从日本神奈川县1000名表面健康、无关联的匿名志愿者的血液中提取的DNA，通过我们开发的方法分析了突变4和6。4神奈川县靠近东京，人口移动的很多，被认为是来自日本各地的混合体，就像东京一样。在这些志愿者中，我们发现6个DNA样本在一个等位基因上单独突变4，但没有突变6。具有WRN突变4或6中任一种的杂合子携带者的患病率估计为6/1000（95%精确中位置信区间：2.4至12.5）。如果考虑到Werner综合征患者中WRN的其他突变，杂合子携带者的患病率预计将高于每1000人中有6人。这一数字预测超过748000杂合子携带者在人口124709000在日本（1996年）。根据他的结果和1987年至1996年的平均出生率，我们得出结论，每年有超过23名婴儿在两个等位基因上都有WRN突变。来自沃纳综合征患者的细胞在遗传上是不稳定的，并且比来自未受影响的个体的细胞对遗传毒性试剂（如4-硝基喹啉-1-氧化物（4 NQO）5和喜树碱）更敏感。4 NQO在一个等位基因处具有WRN突变的细胞中比在没有突变的细胞中产生更强的细胞毒性作用。5因为在日本可能有近一百万杂合子，这样的人可能要小心药物和化学品，如用作抗癌药的喜树碱。我们需要找出杂合子是否容易患上任何与沃纳综合征有关的疾病，包括癌症和糖尿病。
Werner’s syndrome is an autosomal recessive disease that causes premature ageing accompanied by an increased susceptibility to cancer. The causative gene (WRN) codes for a DNA helicase. 1 Worldwide, 1200 patients have been reported from 1904 to 1996; 845 from Japan. Patients are distributed all over Japan. 2 But how widely distributed is the mutated WRN gene in the general population? We previously analysed the mutation in 63 patients with Werner’s syndrome, and found that among 126 chromosomes, 65 (51· 6%) chromosomes had mutation 4 and 22 (17· 5%) had mutation 6, 3 and the rest had other mutations. We focused on mutations 4 and 6. DNA extracted from the blood of 1000 apparently healthy, unlinked anonymous volunteers in Kanagawa prefecture of Japan were analysed for mutations 4 and 6 by a method developed by us. 4 Kanagawa prefecture is near Tokyo with a very mobile population and is considered to be a mix from various parts of Japan, like Tokyo. Mutation of positive DNAs was confirmed by the sequence of the PCR products around the mutation sites.In these volunteers, we found six DNA samples with mutation 4 at one allele alone, but none with mutation 6. The prevalence of heterozygotic carriers with any one of the mutations 4 or 6 of WRN was estimated to be six per 1000 (95% exact mid-p CI: 2· 4 to 12· 5). If the other mutations of WRN in patients with Werner’s syndrome were considered, the prevalence of heterozygotic carriers is expected to be higher than six per 1000. This figure predicts more than 7480 0 0 heterozygous carriers in the population of 1247 09000 in Japan (1996). From his result and the average birth rate between 1987 and 1996, we concluded that more than 23 babies with WRN mutations at both alleles are born each year. Cells from patients with Werner’s syndrome are genetically unstable and more senstive to genotoxic reagents, such as 4-nitroquinoline-1-oxide (4NQO) 5 and camptothecin, than cells from unaffected individuals. 4NQO produces its cytotoxic effects more strongly in cells with a WRN mutation at one allele than in the cells without a mutation. 5 Because in Japan there may be nearly one million heterozygots, such people may have to be careful with drugs and chemicals, such as camptothecin used as an anticancer drug. We need to find out if heterozygotes are liable to any disease related to Werner’s syndrome, including cancers and diabetes.