FOUNDING MUTATIONS AND ALU-MEDIATED RECOMBINATION IN HEREDITARY COLON-CANCER
FOUNDING MUTATIONS AND ALU-MEDIATED RECOMBINATION IN HEREDITARY COLON-CANCER
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DOI：
10.1038/nm1195-1203
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发表时间：
1995-11-01
期刊：
影响因子：
82.9
通讯作者：
PELTOMAKI, P
中科院分区：
文献类型：
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作者：
NYSTROMLAHTI, M;KRISTO, P;PELTOMAKI, P
通过对患有遗传性非息肉病性结直肠癌（HNPCC）的芬兰家庭成员进行筛查，以确定是否存在MSH 2和MLH 1的易感种系突变，我们发现MLH 1中的两种突变加起来占符合国际诊断标准的家族的63%（19/30）。突变1最初被检测为包含外显子16的MLH 1 cDNA中的165个碱基对缺失，显示由3.5-腺苷酸酶基因组缺失组成，最有可能是由腺苷酸介导的重组引起的。突变2破坏外显子6的剪接受体位点。一个简单的诊断测试聚合酶链反应的基础上设计的两种突变。我们的研究结果表明，这两个祖先的创始突变占芬兰HNPCC激酶的大部分，并代表了第一次报告的HNPCC介导的重组导致一个普遍的，显性遗传的癌症易感性。
By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.