Functional characterization of MLH1 missense variants identified in lynch syndrome patients
Functional characterization of MLH1 missense variants identified in lynch syndrome patients
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DOI：
10.1002/humu.22153
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发表时间：
2012-12-01
期刊：
影响因子：
3.9
通讯作者：
Rasmussen, Lene Juel
中科院分区：
文献类型：
--
作者：
Andersen, Sofie Dabros;Liberti, Sascha Emilie;Rasmussen, Lene Juel
人类DNA错配修复（MMR）基因MSH 2和MLH 1中的种系突变与遗传性癌症疾病Lynch综合征（LS）相关，也称为遗传性非息肉病性结直肠癌或HNPCC。在疑似LS患者中发现的一部分MSH 2和MLH 1突变引起单个氨基酸取代。许多这些变异体的致病性方面的功能后果尚不清楚。我们已经研究了在LS家族中发现的一组MLH 1错义突变的功能，通过在功能测定中测试变体蛋白，解决亚细胞定位，以及与二聚体伴侣PMS 2和MMR相关核酸外切酶1的蛋白质相互作用。我们发现，一个显着比例的检查变异蛋白质有功能缺陷，无论是在亚细胞定位或蛋白质-蛋白质相互作用，这是怀疑导致在患者中观察到的癌症表型。此外，获得的结果与报告的MMR活性以及大多数变体的计算机模拟分析密切相关。Mutat 33：16471655，2012. (c)2012 Wiley Periodicals，Inc.
Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and proteinprotein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or proteinprotein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants. Hum Mutat 33:16471655, 2012. (c) 2012 Wiley Periodicals, Inc.