Verselis S J, Rheinwald J G, Fraumeni J F, Li F P
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA 02115, USA.
Oncogene. 2000 Aug 31;19(37):4230-5. doi: 10.1038/sj.onc.1203758.
Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with Li-Fraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-specific DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations affected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9. These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families. Oncogene (2000) 19, 4230 - 4235
在患有李-弗劳梅尼综合征的家族中，p53肿瘤抑制基因的种系突变易导致多种癌症。迄今为止观察到的大多数种系p53突变会导致该蛋白中央序列特异性DNA结合域中的氨基酸替换。然而，在这个保守的核心区域之外，我们在三个李-弗劳梅尼综合征家族中发现了调节前体mRNA剪接的序列中的新改变。两个剪接位点突变影响了内含子1和9的剪接供体位点的共有序列，并在正常细胞中产生了不稳定的变异转录本。内含子9剪接受体位点的第三个突变导致在内含子9的一个隐蔽接受位点处发生剪接。这些剪接位点改变强调了在李-弗劳梅尼综合征家族中检查p53基因的非编码区和非翻译区种系突变的必要性。《癌基因》（2000年）第19卷，4230 - 4235页
