Mutation deep within an intron of MSH2 causes Lynch syndrome.
Mutation deep within an intron of MSH2 causes Lynch syndrome.
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DOI：
10.1007/s10689-011-9427-0
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发表时间：
2011-06
期刊：
影响因子：
2.2
通讯作者：
Young JP
中科院分区：
文献类型：
--
作者：
Clendenning M;Buchanan DD;Walsh MD;Nagler B;Rosty C;Thompson B;Spurdle AB;Hopper JL;Jenkins MA;Young JP
Lynch综合征是一种可遗传的癌症易感性，是由DNA错配修复家族基因的种系突变引起的，通过检测肿瘤样本中这些基因中至少一个的表达缺失，可以在年轻发病的癌症患者中快速识别。迄今为止，这种致病突变只在外显子和剪接位点区域被发现。虽然这种方法在大多数家庭中是成功的，但仍有相当多的家庭没有发现突变。为了解决这种情况，我们使用了另一种突变发现程序，包括对肿瘤中丢失基因的位点进行单倍型分析，并描绘分离的单倍型，然后对剪接畸变进行调查，以发现位于常规检查突变的基因组区域之外的隐剪接位点。在本报告中，我们发现MSH2基因外显子2上游478 bp的内含子突变通过产生新的剪接供体位点并随后激活假外显子而导致Lynch综合征，因此强调了在常规程序无法发现突变的家庭中需要更广泛的测序方法。
Lynch syndrome, a heritable form of cancer predisposition, is caused by germline mutations within genes of the DNA mismatch repair family, and can be rapidly identified in young onset cancer patients through the detection of loss of expression of at least one of these genes in tumour samples. To date, such causative mutations have only been identified within exonic and splice site regions. Though this approach has been successful in the majority of families, a considerable number remain in which no mutation has been found. To address this situation, we used an alternative mutation discovery procedure which involved haplotype analysis of the locus containing the gene lost in the tumour and delineation of segregating haplotypes, followed by an investigation of splicing aberrations to uncover cryptic splice sites which lay outside the genomic regions routinely examined for mutations. In this report, we show that an intronic mutation 478 bp upstream of exon 2 in the MSH2 gene causes Lynch syndrome through creation of a novel splice donor site with subsequent pseudoexon activation, thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation.