Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene
Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene
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DOI：
10.1038/sj.onc.1203447
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发表时间：
2000-03-23
期刊：
影响因子：
8
通讯作者：
Izzo, P
中科院分区：
文献类型：
--
作者：
De Rosa, M;Fasano, C;Izzo, P
特科特综合征是一种遗传性疾病，其特征是原发性脑肿瘤和结肠癌和/或多发性结直肠腺瘤同时存在。我们报告了一个没有父母近亲关系的特科特家族，其中两个受影响的姐妹，其父母没有肿瘤病史，分别死于脑肿瘤和结直肠肿瘤，并且在很小的时候就去世了。先证者在肿瘤和正常结肠粘膜中均具有严重的微卫星不稳定性（MIN）表型，并且在结直肠肿瘤中存在TGFβ-RII和APC基因突变。我们在 PMS2 基因内发现了两个种系突变：外显子 11 中的 G 缺失 (1221delG) 和外显子 14 中的四碱基对缺失 (2361delCTTC)，两者均遗传自患者未受影响的父母。这些结果代表了第一个证据，证明 PMS2 中的两个种系移码突变（一种很少参与 HNPCC 的 MMR 基因）本身并不致病，但当在复合杂合子中同时发生时，就会变得致病。PMS2 基因中两个突变的复合杂合性对于蛋白质 PMS2 在错配修复机制中的作用以及高危家庭成员的症状前分子诊断具有影响。此外，我们的数据支持并扩大了正常组织中 DNA 高度不稳定性可能引发该综合征癌症发展的观点。
Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGF beta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote, The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.