{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T20:44:15Z","timestamp":1789937055655,"version":"4.0.1"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2013,9,10]],"date-time":"2013-09-10T00:00:00Z","timestamp":1378771200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0074766","type":"journal-article","created":{"date-parts":[[2013,9,11]],"date-time":"2013-09-11T09:21:16Z","timestamp":1378891276000},"page":"e74766","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Functional Analysis in Mouse Embryonic Stem Cells Reveals Wild-Type Activity for Three Msh6 Variants Found in Suspected Lynch Syndrome Patients"],"prefix":"10.1371","volume":"8","author":[{"given":"Eva A. L.","family":"Wielders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellen","family":"Houlleberghs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6zde","family":"Isik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hein","family":"te Riele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2013,9,10]]},"reference":[{"key":"ref1","first-page":"801","article-title":"Genetic susceptibility to non-polyposis colorectal cancer","volume":"36","author":"HT Lynch","year":"1999","journal-title":"J Med Genet"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"4486","DOI":"10.1200\/JCO.2004.02.033","article-title":"Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium","volume":"22","author":"J Plaschke","year":"2004","journal-title":"J Clin Oncol"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/jnci\/djp473","article-title":"Risks of Lynch syndrome cancers for MSH6 mutation carriers","volume":"102","author":"L Baglietto","year":"2010","journal-title":"J Natl Cancer Inst"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1001\/jama.296.12.1507","article-title":"Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review","volume":"296","author":"NM Lindor","year":"2006","journal-title":"JAMA"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/jnci\/djh034","article-title":"Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability","volume":"96","author":"A Umar","year":"2004","journal-title":"J Natl Cancer Inst"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1086\/302612","article-title":"Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations","volume":"65","author":"Y Wu","year":"1999","journal-title":"Am J Hum Genet"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1038\/sj.bjc.6605988","article-title":"Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats","volume":"103","author":"JF You","year":"2010","journal-title":"Br J Cancer"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/13773","article-title":"Familial endometrial cancer in female carriers of MSH6 germline mutations","volume":"23","author":"J Wijnen","year":"1999","journal-title":"Nat Genet"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrm1907","article-title":"The multifaceted mismatch-repair system","volume":"7","author":"J Jiricny","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/15544","article-title":"HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions","volume":"23","author":"N de Wind","year":"1999","journal-title":"Nat Genet"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/humu.21438","article-title":"LOVD v.2.0: the next generation in gene variant databases","volume":"32","author":"IF Fokkema","year":"2011","journal-title":"Hum Mutat"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1002\/humu.20735","article-title":"Accurate classification of MLH1\/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)","volume":"29","author":"EC Chao","year":"2008","journal-title":"Hum Mutat"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1423-0127-16-42","article-title":"Investigation on the role of nsSNPs in HNPCC genes - a bioinformatics approach","volume":"16","author":"CG Doss","year":"2009","journal-title":"J Biomed Sci"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1002\/humu.20580","article-title":"Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes","volume":"28","author":"J Ou","year":"2007","journal-title":"Hum Mutat"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1093\/nar\/gkl896","article-title":"Generation of a mouse mutant by oligonucleotide-mediated gene modification in ES cells","volume":"34","author":"M Aarts","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/humu.21448","article-title":"Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells","volume":"32","author":"EA Wielders","year":"2011","journal-title":"Hum Mutat"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/326292a0","article-title":"HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells","volume":"326","author":"M Hooper","year":"1987","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/0092-8674(95)90319-4","article-title":"Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer","volume":"82","author":"N de Wind","year":"1995","journal-title":"Cell"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/348649a0","article-title":"Consecutive inactivation of both alleles of the pim-1 proto-oncogene by homologous recombination in embryonic stem cells","volume":"348","author":"H te Riele","year":"1990","journal-title":"Nature"},{"key":"ref20","first-page":"248","article-title":"Mouse models for hereditary nonpolyposis colorectal cancer","volume":"58","author":"N de Wind","year":"1998","journal-title":"Cancer Res"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/mc.20146","article-title":"Use of mononucleotide repeat markers for detection of microsatellite instability in mouse tumors","volume":"44","author":"JW Bacher","year":"2005","journal-title":"Mol Carcinog"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1038\/sj.onc.1205395","article-title":"Methylation tolerance in mismatch repair proficient cells with low MSH2 protein level","volume":"21","author":"N Claij","year":"2002","journal-title":"Oncogene"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"5128","DOI":"10.1073\/pnas.89.11.5128","article-title":"Highly efficient gene targeting in embryonic stem cells through homologous recombination with isogenic DNA constructs","volume":"89","author":"H te Riele","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s00439-005-0118-5","article-title":"MUTYH and the mismatch repair system: partners in crime?","volume":"119","author":"RC Niessen","year":"2006","journal-title":"Hum Genet"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3995","DOI":"10.1038\/sj.onc.1208569","article-title":"BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes","volume":"24","author":"E Domingo","year":"2005","journal-title":"Oncogene"},{"key":"ref26","first-page":"5068","article-title":"Germ-line msh6 mutations in colorectal cancer families","volume":"59","author":"RD Kolodner","year":"1999","journal-title":"Cancer Res"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00439-002-0866-4","article-title":"Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?","volume":"112","author":"R Kariola","year":"2003","journal-title":"Hum Genet"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1128\/MCB.12.5.2391","article-title":"Production of homozygous mutant ES cells with a single targeting construct","volume":"12","author":"RM Mortensen","year":"1992","journal-title":"Mol Cell Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/ng1294-405","article-title":"Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer","volume":"8","author":"A Hemminki","year":"1994","journal-title":"Nat Genet"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1038\/sj.onc.1210038","article-title":"No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer","volume":"26","author":"S Tuupanen","year":"2007","journal-title":"Oncogene"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"7585","DOI":"10.1038\/sj.onc.1205968","article-title":"Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers","volume":"21","author":"ST Yuen","year":"2002","journal-title":"Oncogene"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"6853","DOI":"10.1158\/1078-0432.CCR-05-0726","article-title":"High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes","volume":"11","author":"MO Woods","year":"2005","journal-title":"Clin Cancer Res"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/humu.22000","article-title":"A Rapid and Cell-Free Assay to Test the Activity of Lynch Syndrome-Associated MSH2 and MSH6 Missense Variants","volume":"33","author":"M Drost","year":"2012","journal-title":"Hum Mutat"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/sj.bjc.6605531","article-title":"MutSbeta exceeds MutSalpha in dinucleotide loop repair","volume":"102","author":"J Kantelinen","year":"2010","journal-title":"Br J Cancer"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/humu.21409","article-title":"Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants","volume":"32","author":"M Kansikas","year":"2011","journal-title":"Hum Mutat"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1093\/hmg\/11.11.1303","article-title":"Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome","volume":"11","author":"R Kariola","year":"2002","journal-title":"Hum Mol Genet"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.1158\/1078-0432.CCR-10-1491","article-title":"MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer","volume":"16","author":"MD Gir\u00e1ldez","year":"2010","journal-title":"Clin Cancer Res"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"6616","DOI":"10.1128\/MCB.18.11.6616","article-title":"Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer","volume":"18","author":"S Guerrette","year":"1998","journal-title":"Mol Cell Biol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/ng.283","article-title":"Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1","volume":"41","author":"MJ Ligtenberg","year":"2009","journal-title":"Nat Genet"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0074766","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,10,20]],"date-time":"2018-10-20T07:03:02Z","timestamp":1540018982000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0074766"}},"subtitle":[],"editor":[{"given":"Amanda\u00a0Ewart","family":"Toland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,9,10]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2013,9,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0074766","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,10]]}}}