Mismatch repair gene PMS2:: Disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation
Mismatch repair gene PMS2:: Disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation
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DOI：
10.1158/0008-5472.can-03-2879
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
de la Chapelle, A
中科院分区：
文献类型：
--
作者：
Nakagawa, H;Lockman, JC;de la Chapelle, A
由错配修复 (MMR) 蛋白 MLH1 和 PMS2 形成的 MutLalpha 异二聚体是 MMR 复合物的主要组成部分，但 PMS2 基因的突变在遗传性非息肉病性结直肠癌的病因学中很少见。来自五个已发表病例的证据表明，与克努森原理相反，PMS2 突变只有在种系双等位或异常表达时才会导致遗传性非息肉病性结直肠癌或特科特综合征。作为 PMS2 突变的候选者，我们选择了 7 名结肠肿瘤免疫组织化学染色 PMS2 阴性、MLH1 阳性的患者。转化为单倍体后，在两名患者中发现了 PMS2 的截短种系突变（2192delTAACT 和外显子 8 缺失）。根据 Western 分析，这些突变消除了生殖细胞中的 PMS2 蛋白。在另外两名患者中，来自一个等位基因的 PMS2 蛋白也被消除。检测到新的或先前描述的 PMS2 错义变体，但其致病性尚未确定。我们检测并表征了一个新转录本 PMS2CL，它与 PMS2 的外显子 9 和 11-15 具有 98% 的序列同一性，并且源自染色体 7p 中靠近 PMS2 的基因座。未检测到其预测的蛋白质产物。因此，除了先前描述的几种类似于PMS2的5'端的PMS2相关基因之外，至少一种相关基因类似于PMS2的3'端。总之，可检测的和目前未定义的种系突变都是有害的，并通过两次打击机制产生对癌症的易感性。旁系同源基因干扰突变检测，导致 PMS2 突变诊断不足。 PMS2 中的突变检测需要单倍体 DNA。
The MutLalpha heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary non-polyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary non-polyposis colorectal cancer or Turcot syndrome only when they are, biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein product was not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.