Department of Clinical Oncology, Institute of Development, Aging and Cancer, and Tohoku University Hospital, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
Fam Cancer. 2012 Dec;11(4):559-64. doi: 10.1007/s10689-012-9547-1.
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, characterized by predisposition to colorectal cancer and other associated cancers, is an autosomal-dominant disorder mainly caused by germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, and MSH6. Some mutations that disrupt splice donor or acceptor sites cause aberrant mRNA splicing. These mutations are generally considered as pathogenic ones, however, it is sometimes uneasy to accurately predict their pathogenicity without functional assays, particularly when the mutation is a single nucleotide substitution. In this report, we describe a 25-year-old patient with Lynch syndrome who carries a germline variant in a splice donor site of the MLH1 gene (c.790 + 5 G > T), which was first detected among Asian populations. The immunohistochemical analysis revealed loss of MLH1 protein expression in the tumor. Our splicing assay confirmed that the intronic MLH1 variant actually caused aberrant splicing, supporting its pathogenic effect. Our data accumulate more information on the genotype-phenotype relationships in patients with Lynch syndrome.
林奇综合征，又称遗传性非息肉病性结直肠癌，其特征为易患结直肠癌和其他相关癌症，是一种常染色体显性遗传疾病，主要由 DNA 错配修复（MMR）基因如 MLH1、MSH2 和 MSH6 的种系突变引起。一些导致剪接受体或供体位点异常的突变会导致异常的 mRNA 剪接。这些突变通常被认为是致病性的，但在没有功能检测的情况下，特别是当突变是单核苷酸取代时，有时难以准确预测其致病性。在本报告中，我们描述了一位 25 岁的林奇综合征患者，其 MLH1 基因（c.790+5G>T）的剪接受体位点存在种系变异，该变异首先在亚洲人群中被发现。免疫组化分析显示肿瘤中 MLH1 蛋白表达缺失。我们的剪接分析证实，内含子 MLH1 变异实际上导致了异常剪接，支持其致病性效应。我们的数据为林奇综合征患者的基因型-表型关系积累了更多信息。
