A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families.
A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families.
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发表时间：
2001-10
期刊：
影响因子：
11.2
通讯作者：
A. Stella;A. Wagner;K. Shito;S. Lipkin;P. Watson;G. Guanti;H. Lynch;R. Fodde;B. Liu
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文献类型：
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作者：
A. Stella;A. Wagner;K. Shito;S. Lipkin;P. Watson;G. Guanti;H. Lynch;R. Fodde;B. Liu
DNA 错配修复基因 MSH2 和 MLH1 的种系突变是导致大多数遗传性非息肉病性结直肠癌 (HNPCC) 家族的原因。常见的突变机制是破坏 MLH1 和 MSH2 mRNA 剪接。这种破坏会产生缺乏特定编码外显子的异常 mRNA（外显子跳跃）。在这里，我们报告了北美起源的三个 HNPCC 家族中由密码子 461 处的 AAG 到 TAG 无义突变引起的 MLH1 外显子 12 的新跳跃。无义密码子是在三个不相关家族的保守单倍型中发现的，似乎代表了一个创始人突变。这种跳跃产生了缺少外显子 12 的异常 MLH1 mRNA 转录本。密码子 461 无义突变对外显子 12 跳跃的影响是显而易见的，即使它被放置在包含完全不同编码序列的小基因构建体中。值得注意的是，无义突变对外显子跳跃的影响是不完整的。因此，还产生了包含无义密码子的第二个异常 MLH1 转录物。尽管后一种转录本不稳定，可能是由于无义介导的 mRNA 衰减，但两种异常转录本似乎都不会影响野生型 MLH1 mRNA 的稳定性。这项研究表明，MLH1 密码子 461 处的种系无义突变破坏了正常的 MLH1 mRNA 加工，并且外显子跳跃是这些 HNPCC 家族发病机制的基础。
Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 are responsible for the majority of hereditary nonpolyposis colorectal cancer (HNPCC) families. A common mutation mechanism is to disrupt MLH1 and MSH2 mRNA splicing. The disruption creates aberrant mRNAs lacking specific coding exons (exon skipping). Here, we report a novel skipping of MLH1 exon 12 caused by an AAG to TAG nonsense mutation at codon 461 in three HNPCC families of North American origins. The nonsense codon was found in a conserved haplotype in the three unrelated families and seems to represent a founder mutation. The skipping created an aberrant MLH1 mRNA transcript lacking exon 12. The effect of the codon 461 nonsense mutation on exon 12 skipping is evident even though it was placed in a minigene construct containing entirely different coding sequences. Notably, the effect of the nonsense mutation on exon skipping is incomplete. Accordingly, a second aberrant MLH1 transcript encompassing the nonsense codon is also produced. Whereas the latter transcript is unstable, presumably because of nonsense-mediated mRNA decay, neither of the aberrant transcripts seems to affect the stability of wild-type MLH1 mRNA. This study demonstrates that the germ-line nonsense mutation at codon 461 of MLH1 disrupts normal MLH1 mRNA processing, and that exon skipping underlies pathogenesis in these HNPCC families.