Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies

被引：23

作者：

Hardt, Karin ^{[1
,2
]}

Heick, Sven Boris ^{[3
]}

Betz, Beate ^{[1
,2
]}

Goecke, Timm ^{[1
,2
]}

Yazdanparast, Haniyeh ^{[1
,2
]}

Kueppers, Robin ^{[1
,2
]}

Servan, Kati ^{[1
,2
]}

Steinke, Verena ^{[4
]}

Rahner, Nils ^{[4
]}

Morak, Monika ^{[5
,6
]}

Holinski-Feder, Elke ^{[5
,6
]}

Engel, Christoph ^{[7
]}

Moeslein, Gabriela ^{[8
]}

Schackert, Hans-Konrad ^{[9
]}

Doeberitz, Magnus von Knebel ^{[10
]}

Pox, Christian ^{[11
]}

Propping, Peter ^{[4
]}

Hegemann, Johannes H. ^{[3
]}

Royer-Pokora, Brigitte ^{[1
,2
]}

机构：

[1] Univ Dusseldorf, Inst Human Genet & Anthropol, D-40001 Dusseldorf, Germany

[2] Univ Hosp Duesseldorf, D-40001 Dusseldorf, Germany

[3] Univ Dusseldorf, Inst Funct Microbial Genom, D-40001 Dusseldorf, Germany

[4] Univ Hosp Bonn, Inst Human Genet, Bonn, Germany

[5] Univ Munich, Univ Hosp, Ctr Med Genet, Munich, Germany

[6] MGZ, Munich, Germany

[7] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[8] HELIOS St Josefs Hosp, Dept Surg, Bochum, Germany

[9] Tech Univ Dresden, Dept Surg Res, D-8027 Dresden, Germany

[10] Univ Heidelberg Hosp, Inst Appl Tumor Biol, Heidelberg, Germany

[11] Ruhr Univ Bochum, Dept Med, Knappschaftskrankenhaus, Bochum, Germany

来源：

FAMILIAL CANCER | 2011年 / 10卷 / 02期

关键词：

HNPCC; MLH1; Missense variants; Variants of unclassified significance; DNA MISMATCH REPAIR; NONPOLYPOSIS COLORECTAL-CANCER; MLH1; MUTATIONS; COLON-CANCER; MUTS-ALPHA; PROTEIN; YEAST; POLYMORPHISMS; EXPRESSION; INTERFACE;

D O I：

10.1007/s10689-011-9431-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A (14) reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral.

引用

页码：273 / 284

页数：12

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