Machackova E, Damborsky J, Valik D, Foretova L
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 656 53, Czech Republic.
Hum Mutat. 2001 Dec;18(6):545. doi: 10.1002/humu.1232.
Germline mutations in breast cancer susceptibility genes, BRCA1 and BRCA2, are responsible for a substantial proportion of high-risk breast and breast/ovarian cancer families. To characterize the spectrum of BRCA1 and BRCA2 mutations, we screened Czech families with breast/ovarian cancer using the non-radioactive protein truncation test, heteroduplex analysis and direct sequencing. In a group of 100 high-risk breast and breast/ovarian cancer families, four novel frame shift mutations were identified in BRCA1 and BRCA2 genes. In BRCA1, two novel frame shift mutations were identified as 3761-3762delGA and 2616-2617ins10; in BRCA2, two novel frame shift mutations were identified as 5073-5074delCT and 6866delC. Furthermore, a novel missense substitution M18K in BRCA1 gene in a breast/ovarian cancer family was identified which lies adjacent just upstream of the most highly conserved C3HC4 RING zinc finger motif. To examine the tertiary structure of the RING zinc finger domain and possible effects of M18K substitution on its stability, we used threading techniques according to the crystal structure of RAG1 dimerization domain of the DNA-binding protein.
乳腺癌易感基因BRCA1和BRCA2的种系突变是导致相当一部分高危乳腺癌和乳腺癌/卵巢癌家族发病的原因。为了明确BRCA1和BRCA2突变谱，我们使用非放射性蛋白质截短试验、异源双链分析和直接测序技术，对捷克的乳腺癌/卵巢癌家族进行了筛查。在一组100个高危乳腺癌和乳腺癌/卵巢癌家族中，在BRCA1和BRCA2基因中发现了4种新的移码突变。在BRCA1中，两种新的移码突变被鉴定为3761 - 3762delGA和2616 - 2617ins10；在BRCA2中，两种新的移码突变被鉴定为5073 - 5074delCT和6866delC。此外，在一个乳腺癌/卵巢癌家族的BRCA1基因中发现了一种新的错义替代M18K，它位于最保守的C3HC4 RING锌指基序上游紧邻处。为了研究RING锌指结构域的三级结构以及M18K替代对其稳定性的可能影响，我们根据DNA结合蛋白RAG1二聚化结构域的晶体结构，使用了穿线技术。
