{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:46:19Z","timestamp":1789850779718,"version":"4.0.1"},"reference-count":21,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2008,6,2]],"date-time":"2008-06-02T00:00:00Z","timestamp":1212364800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp;amp; Cancer"],"published-print":{"date-parts":[[2008,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>MLH3<\/jats:italic> gene is one of the five mismatch repair (MMR) genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). Eighteen different inherited <jats:italic>MLH3<\/jats:italic> mutations have been reported as pathogenic in an international mutation database. In several cases, a mutation was found in a patient without a family history suggestive of inherited cancer susceptibility. In some cases, a similar mutation was also found in sporadic patients and\/or healthy controls. Four patients carried an <jats:italic>MLH3<\/jats:italic> mutation together with another inherited MMR gene variation. No functional analyses have been performed to assess the pathogenicity of these 18 mutations. <jats:italic>MLH3<\/jats:italic> has been assumed to be less important in MMR than the other HNPCC susceptibility genes <jats:italic>MSH2, MSH6, MLH1<\/jats:italic>, and <jats:italic>PMS2<\/jats:italic>, and accordingly a low\u2010risk gene for colorectal cancer (CRC). To assess the significance of the inherited sequence variations in <jats:italic>MLH3<\/jats:italic>, we functionally characterized seven missense mutations (Q24E, R647C, S817G, G933C, W1276R, A1394T, E1451K) scattered throughout the MLH3 polypeptide. The mutations were found in CRC or endometrial cancer patients and reported as pathogenic. Our study showed that the seven mutated MLH3 proteins, in complex with their counterpart MLH1 (MutL\u03b3), repaired mismatches as the wild type MutL\u03b3 but worse than a heterodimer of MLH1 and PMS2 (MutL\u03b1). The results confirm that MutL\u03b3 is a less efficient MMR complex than MutL\u03b1 and show that the <jats:italic>MLH3<\/jats:italic> mutations alone do not interfere with MMR. Further studies are needed to evaluate the pathogenicity of <jats:italic>MLH3<\/jats:italic> mutations in compound with other MMR mutations. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.20581","type":"journal-article","created":{"date-parts":[[2008,6,2]],"date-time":"2008-06-02T17:22:08Z","timestamp":1212427328000},"page":"803-809","source":"Crossref","is-referenced-by-count":27,"title":["The first functional study of <i>MLH3<\/i> mutations found in cancer patients"],"prefix":"10.1002","volume":"47","author":[{"given":"Mari K.","family":"Korhonen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Vuorenmaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Nystr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,6,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80717-5"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2528"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0742"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M509701200"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12404"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.23.8860"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.05.039"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2007.04.011"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200506170"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(99)80013-6"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.8.1695"},{"key":"e_1_2_6_13_1","first-page":"351","article-title":"Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low\u2010risk gene in HNPCC","volume":"17","author":"Korhonen MK","year":"2007","journal-title":"Oncol Rep"},{"key":"e_1_2_6_14_1","first-page":"1894","article-title":"The role of hMLH3 in familial colorectal cancer","volume":"63","author":"Liu H\u2010X","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i33.5281"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.1225"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.06.005"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.15.1697"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0248"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.13914"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-137"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.027"}],"container-title":["Genes, Chromosomes and Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fgcc.20581","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.20581","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T19:56:07Z","timestamp":1700078167000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gcc.20581"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,6,2]]},"references-count":21,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2008,9]]}},"alternative-id":["10.1002\/gcc.20581"],"URL":"https:\/\/doi.org\/10.1002\/gcc.20581","archive":["Portico"],"relation":{},"ISSN":["1045-2257","1098-2264"],"issn-type":[{"value":"1045-2257","type":"print"},{"value":"1098-2264","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,6,2]]}}}