The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex.
The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex.
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DOI：
10.1002/mc.20838
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发表时间：
2012-08
影响因子：
4.6
通讯作者：
Heinen, Christopher D.
中科院分区：
文献类型：
--
作者：
Cyr, Jennifer L.;Brown, Graham D.;Stroop, Jennifer;Heinen, Christopher D.
林奇综合征 (LS) 是由 DNA 错配修复 (MMR) 基因种系突变引起的。 M M R 识别并修复 DNA 错配和小插入/删除环。 MMR 基因变异携带者患结直肠癌、子宫内膜癌、卵巢癌和其他结肠外癌的风险很高。我们报告了一名卵巢癌患者，该患者携带种系 MSH2 c.1A>C 变体，该变体改变了翻译起始密码子。先前已经描述了影响 LS 相关恶性肿瘤的 MSH2 起始密码子的突变。然而，患者往往缺乏明确的 LS 家族史，而且他们的肿瘤往往无法表现出微卫星不稳定性，这是 LS 的一个标志性特征。因此，起始密码子变异的致病性仍然不确定。据预测，MSH2 起始密码子的丢失将导致从下游框内 AUG 翻译而来的截短蛋白质，该蛋白质将缺少前 25 个氨基酸。因此，我们纯化了重组MSH2(NΔ25)-MSH6和MSH2(NΔ25)-MSH3，以在体外检查它们的DNA损伤识别和腺苷核苷酸加工功能。我们发现 MSH2(NΔ25) 突变体赋予 MSH2-MSH6 明显的生化缺陷，但对 MSH2-MSH3 没有显着影响。我们证实，MSH2 c.1A>C cDNA 的表达会导致人类细胞中产生多种蛋白质产物，其中可能包括截短形式和全长形式的 MSH2。体内 MMR 测定显示这些细胞的 MMR 效率略有降低。这些数据表明，MSH2 起始密码子的突变虽然不是强、高风险的疾病等位基因，但可能对疾病表型产生中等影响。
Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. M M R recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS. Therefore, the pathogenicity of start codon variants remains undefined. Loss of the MSH2 start codon has been predicted to result in a truncated protein translated from a downstream in-frame AUG that would lack the first 25 amino acids. We therefore purified recombinant MSH2(NΔ25)-MSH6 and MSH2(NΔ25)-MSH3 to examine their DNA lesion recognition and adenosine nucleotide processing functions in vitro. We found that the MSH2(NΔ25) mutant confers distinct biochemical defects on MSH2-MSH6, but does not have a significant effect on MSH2-MSH3. We confirmed that expression of the MSH2 c.1A>C cDNA results in the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. An in vivo MMR assay revealed a slight reduction in MMR efficiency in these cells. These data suggest that mutation of the MSH2 initiation codon, while not a strong, high-risk disease allele, may have a moderate impact on disease phenotype.
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影响因子：
4.8
作者：
Martik, D;Baitinger, C;Modrich, P
通讯作者：
Modrich, P
影响因子：
3.9
作者：
Mastrocola, Adam S.;Heinen, Christopher D.
通讯作者：
Heinen, Christopher D.
DOI：
10.1016/s0003-3995(02)01115-2
发表时间：
2002-04-01
期刊：
ANNALES DE GENETIQUE
影响因子：
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作者：
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通讯作者：
Hamelin, R
影响因子：
4.8
作者：
Gerashchenko, Maxim V.;Su, Dan;Gladyshev, Vadim N.
通讯作者：
Gladyshev, Vadim N.
影响因子：
5.3
作者：
Guerrette, S;Wilson, T;Fishel, R
通讯作者：
Fishel, R