Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Hum Mutat. 2012 Jul;33(7):1051-5. doi: 10.1002/humu.22092. Epub 2012 Apr 30.
Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders.
错配修复基因 PMS2 的种系杂合突变使携带者易患林奇综合征，这是一种常染色体显性遗传的癌症易感性。在这里，我们提出了一种 LINE-1 介导的 PMS2 逆转座插入，作为林奇综合征的一种新突变类型。这种插入物通过对患者基因组 DNA 的 Southern 印迹分析检测到，其特征是 2.2kb 长的 5'截断 SVA_F 元件。这种插入物不能通过目前仅限于 MLPA 和直接基因组 DNA 焦磷酸测序的诊断检测来检测。只有在抑制无意义介导的 RNA 衰变的培养淋巴细胞的 RNA 中才能解决这种插入的分子性质。我们的报告说明了在检测这种突变类型时遇到的技术问题。特别是由于在基因组 DNA 中优先扩增较小的野生型等位基因，较大的杂合插入物将被忽略，并且在常染色体显性疾病的突变谱中可能被低估。
