2o8f

Structural highlights

Disease

[MSH6_HUMAN] Defects in MSH6 are the cause of hereditary non-polyposis colorectal cancer type 5 (HNPCC5) [MIM:614350]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. MSH6 mutations appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer. Defects in MSH6 are also found in familial colorectal cancers (suspected or incomplete HNPCC) that do not fulfill the Amsterdam criteria for HNPCC.^{[1] [2] [3] [4] [5] [6] [7] [8]} Defects in MSH6 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. Defects in MSH6 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.^[9] [MSH2_HUMAN] Defects in MSH2 are the cause of hereditary non-polyposis colorectal cancer type 1 (HNPCC1) [MIM:120435]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. MSH2 mutations may predispose to hematological malignancies and multiple cafe-au-lait spots.^{[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60]} Defects in MSH2 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.^[61] Defects in MSH2 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089].

Function

[MSH6_HUMAN] Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair.^{[62] [63] [64] [65] [66] [67]} [MSH2_HUMAN] Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis.^{[68] [69] [70] [71] [72] [73] [74]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997 Nov;17(3):271-2. PMID:9354786 doi:10.1038/ng1197-271
2. ↑ Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999 Nov;65(5):1291-8. PMID:10521294 doi:S0002-9297(07)62135-1
3. ↑ Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A. Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet. 1999 Jul-Aug;105(1-2):79-85. PMID:10480359
4. ↑ Wu Y, Berends MJ, Sijmons RH, Mensink RG, Verlind E, Kooi KA, van der Sluis T, Kempinga C, van dDer Zee AG, Hollema H, Buys CH, Kleibeuker JH, Hofstra RM. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 2001 Oct;29(2):137-8. PMID:11586295 doi:10.1038/ng1001-137
5. ↑ Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R. Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet. 2003 May;72(5):1088-100. Epub 2003 Mar 25. PMID:12658575 doi:10.1086/373963
6. ↑ Plaschke J, Kruger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Moslein G, Ruschoff J, Engel C, Evans G, Schackert HK. Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Hum Mutat. 2004 Mar;23(3):285. PMID:14974087 doi:10.1002/humu.9217
7. ↑ Shin YK, Heo SC, Shin JH, Hong SH, Ku JL, Yoo BC, Kim IJ, Park JG. Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat. 2004 Oct;24(4):351. PMID:15365995 doi:10.1002/humu.9277
8. ↑ Drost M, Zonneveld JB, van Hees S, Rasmussen LJ, Hofstra RM, de Wind N. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. Hum Mutat. 2012 Mar;33(3):488-94. doi: 10.1002/humu.22000. Epub 2011 Dec 29. PMID:22102614 doi:10.1002/humu.22000
9. ↑ Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007 Nov;28(11):1084-90. PMID:17557300 doi:10.1002/humu.20569
10. ↑ Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M, et al.. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993 Dec 17;75(6):1215-25. PMID:8261515
11. ↑ Clark AB, Cook ME, Tran HT, Gordenin DA, Resnick MA, Kunkel TA. Functional analysis of human MutSalpha and MutSbeta complexes in yeast. Nucleic Acids Res. 1999 Feb 1;27(3):736-42. PMID:9889267
12. ↑ Mary JL, Bishop T, Kolodner R, Lipford JR, Kane M, Weber W, Torhorst J, Muller H, Spycher M, Scott RJ. Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. Hum Mol Genet. 1994 Nov;3(11):2067-9. PMID:7874129
13. ↑ Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham JM, French AJ, Halling KC, Schwab M, Goretzki P, Thibodeau SN. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. Hum Mol Genet. 1996 Sep;5(9):1245-52. PMID:8872463
14. ↑ Bubb VJ, Curtis LJ, Cunningham C, Dunlop MG, Carothers AD, Morris RG, White S, Bird CC, Wyllie AH. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996 Jun 20;12(12):2641-9. PMID:8700523
15. ↑ Wijnen J, Khan PM, Vasen H, van der Klift H, Mulder A, van Leeuwen-Cornelisse I, Bakker B, Losekoot M, Moller P, Fodde R. Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet. 1997 Aug;61(2):329-35. PMID:9311737 doi:10.1086/514847
16. ↑ Akiyama Y, Tsubouchi N, Yuasa Y. Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers. Biochem Biophys Res Commun. 1997 Jul 18;236(2):248-52. PMID:9240418 doi:S0006-291X(97)96942-4
17. ↑ Nakahara M, Yokozaki H, Yasui W, Dohi K, Tahara E. Identification of concurrent germ-line mutations in hMSH2 and/or hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds. Cancer Epidemiol Biomarkers Prev. 1997 Dec;6(12):1057-64. PMID:9419403
18. ↑ Beck NE, Tomlinson IP, Homfray T, Frayling I, Hodgson SV, Harocopos C, Bodmer WF. Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria. Hum Genet. 1997 Feb;99(2):219-24. PMID:9048925
19. ↑ Wehner M, Buschhausen L, Lamberti C, Kruse R, Caspari R, Propping P, Friedl W. Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes. Hum Mutat. 1997;10(3):241-4. PMID:9298827 doi:<241::AID-HUMU12>3.0.CO;2-# 10.1002/(SICI)1098-1004(1997)10:3<241::AID-HUMU12>3.0.CO;2-#
20. ↑ Farrington SM, Lin-Goerke J, Ling J, Wang Y, Burczak JD, Robbins DJ, Dunlop MG. Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet. 1998 Sep;63(3):749-59. PMID:9718327 doi:10.1086/301996
21. ↑ Yuan Y, Han HJ, Zheng S, Park JG. Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer. Dis Colon Rectum. 1998 Apr;41(4):434-40. PMID:9559627
22. ↑ Heinimann K, Scott RJ, Buerstedde JM, Weber W, Siebold K, Attenhofer M, Muller H, Dobbie Z. Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer. Cancer. 1999 Jun 15;85(12):2512-8. PMID:10375096
23. ↑ Genuardi M, Carrara S, Anti M, Ponz de Leon M, Viel A. Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2. Eur J Hum Genet. 1999 Oct-Nov;7(7):778-82. PMID:10573010 doi:10.1038/sj.ejhg.5200363
24. ↑ Weber TK, Chin HM, Rodriguez-Bigas M, Keitz B, Gilligan R, O'Malley L, Urf E, Diba N, Pazik J, Petrelli NJ. Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer. JAMA. 1999 Jun 23-30;281(24):2316-20. PMID:10386556
25. ↑ Yuan ZQ, Wong N, Foulkes WD, Alpert L, Manganaro F, Andreutti-Zaugg C, Iggo R, Anthony K, Hsieh E, Redston M, Pinsky L, Trifiro M, Gordon PH, Lasko D. A missense mutation in both hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening. J Med Genet. 1999 Oct;36(10):790-3. PMID:10528862
26. ↑ Nomura S, Sugano K, Kashiwabara H, Taniguchi T, Fukayama N, Fujita S, Akasu T, Moriya Y, Ohhigashi S, Kakizoe T, Sekiya T. Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds. Biochem Biophys Res Commun. 2000 Apr 29;271(1):120-9. PMID:10777691 doi:10.1006/bbrc.2000.2547
27. ↑ Isidro G, Veiga I, Matos P, Almeida S, Bizarro S, Marshall B, Baptista M, Leite J, Regateiro F, Soares J, Castedo S, Boavida MG. Four novel MSH2 / MLH1 gene mutations in portuguese HNPCC families. Hum Mutat. 2000 Jan;15(1):116. PMID:10612836 doi:<116::AID-HUMU24>3.0.CO;2-Q 10.1002/(SICI)1098-1004(200001)15:1<116::AID-HUMU24>3.0.CO;2-Q
28. ↑ Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Mecklin JP, Aaltonen LA, de la Chapelle A. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2000 Jun;18(11):2193-200. PMID:10829038
29. ↑ Kim JC, Kim HC, Roh SA, Koo KH, Lee DH, Yu CS, Lee JH, Kim TW, Lee HL, Beck NE, Bodmer WF. hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer. Cancer Detect Prev. 2001;25(6):503-10. PMID:12132870
30. ↑ Muller-Koch Y, Kopp R, Lohse P, Baretton G, Stoetzer A, Aust D, Daum J, Kerker B, Gross M, Dietmeier W, Holinski-Feder E. Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms? Eur J Med Res. 2001 Nov 20;6(11):473-82. PMID:11726306
31. ↑ Gille JJ, Hogervorst FB, Pals G, Wijnen JT, van Schooten RJ, Dommering CJ, Meijer GA, Craanen ME, Nederlof PM, de Jong D, McElgunn CJ, Schouten JP, Menko FH. Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. Br J Cancer. 2002 Oct 7;87(8):892-7. PMID:12373605 doi:10.1038/sj.bjc.6600565
32. ↑ Furukawa T, Konishi F, Shitoh K, Kojima M, Nagai H, Tsukamoto T. Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma. Cancer. 2002 Feb 15;94(4):911-20. PMID:11920458
33. ↑ Heinen CD, Wilson T, Mazurek A, Berardini M, Butz C, Fishel R. HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions. Cancer Cell. 2002 Jun;1(5):469-78. PMID:12124176
34. ↑ Bisgaard ML, Jager AC, Myrhoj T, Bernstein I, Nielsen FC. Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. Hum Mutat. 2002 Jul;20(1):20-7. PMID:12112654 doi:10.1002/humu.10083
35. ↑ Ward R, Meldrum C, Williams R, Mokany E, Scott R, Turner J, Hawkins N, Burgess B, Groombridge C, Spigelman A. Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer. J Cancer Res Clin Oncol. 2002 Aug;128(8):403-11. Epub 2002 Jul 18. PMID:12200596 doi:10.1007/s00432-002-0361-2
36. ↑ Scartozzi M, Bianchi F, Rosati S, Galizia E, Antolini A, Loretelli C, Piga A, Bearzi I, Cellerino R, Porfiri E. Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol. 2002 Mar 1;20(5):1203-8. PMID:11870161
37. ↑ Kurzawski G, Suchy J, Kladny J, Safranow K, Jakubowska A, Elsakov P, Kucinskas V, Gardovski J, Irmejs A, Sibul H, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Clark J, Gozdz S, Niepsuj S, Slomski R, Plawski A, Lacka-Wojciechowska A, Rozmiarek A, Fiszer-Maliszewska L, Bebenek M, Sorokin D, Stawicka M, Godlewski D, Richter P, Brozek I, Wysocka B, Jawien A, Banaszkiewicz Z, Kowalczyk J, Czudowska D, Goretzki PE, Moeslein G, Lubinski J. Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States. J Med Genet. 2002 Oct;39(10):E65. PMID:12362047
38. ↑ Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R. Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet. 2003 May;72(5):1088-100. Epub 2003 Mar 25. PMID:12658575 doi:10.1086/373963
39. ↑ Chen-Shtoyerman R, Theodor L, Harmati E, Friedman E, Dacka S, Kopelman Y, Sternberg A, Zarivach R, Bar-Meir S, Fireman Z. Genetic analysis of familial colorectal cancer in Israeli Arabs. Hum Mutat. 2003 Apr;21(4):446-7. PMID:12655564 doi:10.1002/humu.9123
40. ↑ Bartosova Z, Fridrichova I, Bujalkova M, Wolf B, Ilencikova D, Krizan P, Hlavcak P, Palaj J, Lukac L, Lukacova M, Boor A, Haider R, Jiricny J, Nystrom-Lahti M, Marra G. Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia. Hum Mutat. 2003 Apr;21(4):449. PMID:12655568 doi:10.1002/humu.9127
41. ↑ Taylor CF, Charlton RS, Burn J, Sheridan E, Taylor GR. Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. Hum Mutat. 2003 Dec;22(6):428-33. PMID:14635101 doi:10.1002/humu.10291
42. ↑ Sun MH, Cai Q, Fu G, Ren S, Mo S, Xu Y, Ding C, Zhang T, Zhu X, Xu X, Min D, Cai S, Luo D, Shi Y, Shi D. Gene symbol: hMSH2. Disease: Hereditary nonpolyposis colorectal cancer. Hum Genet. 2004 Mar;114(4):409. PMID:15046096
43. ↑ Sharp A, Pichert G, Lucassen A, Eccles D. RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1. Hum Mutat. 2004 Sep;24(3):272. PMID:15300854 doi:10.1002/humu.9267
44. ↑ Shin YK, Heo SC, Shin JH, Hong SH, Ku JL, Yoo BC, Kim IJ, Park JG. Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat. 2004 Oct;24(4):351. PMID:15365995 doi:10.1002/humu.9277
45. ↑ Yuan Y, Huang YQ, Cai SR, Song YM, Zheng S, Zhang SZ. Genetic characterization of Chinese hereditary non-polyposis colorectal cancer by DHPLC and multiplex PCR. Jpn J Clin Oncol. 2004 Nov;34(11):660-6. PMID:15613555 doi:10.1093/jjco/hyh121
46. ↑ Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espin E, Armengol M, Hamelin R, Yamamoto H, Hofstra RM, Seruca R, Lindblom A, Peltomaki P, Thibodeau SN, Aaltonen LA, Schwartz S Jr. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004 Sep;41(9):664-8. PMID:15342696 doi:10.1136/jmg.2004.020651
47. ↑ Baudi F, Fersini G, Lavecchia A, Terracciano R, Leone F, Quaresima B, Faniello MC, De Paola L, Doldo P, Cuda G, Costanzo F, Venuta S. A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy. Cancer Lett. 2005 Jun 8;223(2):285-91. Epub 2004 Nov 25. PMID:15896463 doi:10.1016/j.canlet.2004.09.051
48. ↑ Lee SC, Guo JY, Lim R, Soo R, Koay E, Salto-Tellez M, Leong A, Goh BC. Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Clin Genet. 2005 Aug;68(2):137-45. PMID:15996210 doi:10.1111/j.1399-0004.2005.00469.x
49. ↑ Wehner M, Mangold E, Sengteller M, Friedrichs N, Aretz S, Friedl W, Propping P, Pagenstecher C. Hereditary nonpolyposis colorectal cancer: pitfalls in deletion screening in MSH2 and MLH1 genes. Eur J Hum Genet. 2005 Aug;13(8):983-6. PMID:15870828 doi:10.1038/sj.ejhg.5201421
50. ↑ Otway R, Tetlow N, Hornby J, Doe WF, Kohonen-Coriah MR. Gene symbol: MSH2. Disease: Hereditary nonpolyposis colorectal cancer. Hum Genet. 2005 May;116(6):539. PMID:15991316
51. ↑ Kurzawski G, Suchy J, Lener M, Klujszo-Grabowska E, Kladny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Gozdz S, Niepsuj S, Slomski R, Plawski A, Lacka-Wojciechowska A, Rozmiarek A, Fiszer-Maliszewska L, Bebenek M, Sorokin D, Sasiadek MM, Stembalska A, Grzebieniak Z, Kilar E, Stawicka M, Godlewski D, Richter P, Brozek I, Wysocka B, Limon J, Jawien A, Banaszkiewicz Z, Janiszewska H, Kowalczyk J, Czudowska D, Scott RJ, Lubinski J. Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). Clin Genet. 2006 Jan;69(1):40-7. PMID:16451135 doi:CGE550
52. ↑ Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomaki P, Mangold E, de la Chapelle A, Greenblatt M, Nystrom M. Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22. PMID:17101317 doi:10.1053/j.gastro.2006.08.044
53. ↑ Leonardis D. Gene symbol: msh2. Disease: hereditary nonpolyposis colorectal cancer. Hum Genet. 2006 Jul;119(6):675. PMID:17128465
54. ↑ Ramsoekh D, Wagner A, van Leerdam ME, Dinjens WN, Steyerberg EW, Halley DJ, Kuipers EJ, Dooijes D. A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut. 2008 Nov;57(11):1539-44. doi: 10.1136/gut.2008.156695. Epub 2008 Jul 14. PMID:18625694 doi:10.1136/gut.2008.156695
55. ↑ Ollila S, Dermadi Bebek D, Jiricny J, Nystrom M. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat. 2008 Nov;29(11):1355-63. PMID:18951462 doi:10.1002/humu.20893
56. ↑ Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frebourg T, Tosi M. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat. 2008 Dec;29(12):1412-24. PMID:18561205 doi:10.1002/humu.20796
57. ↑ Belvederesi L, Bianchi F, Galizia E, Loretelli C, Bracci R, Catalani R, Amati M, Cellerino R. MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system. Hum Mutat. 2008 Nov;29(11):E296-309. PMID:18781619 doi:10.1002/humu.20875
58. ↑ Lutzen A, de Wind N, Georgijevic D, Nielsen FC, Rasmussen LJ. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res. 2008 Oct 14;645(1-2):44-55. doi: 10.1016/j.mrfmmm.2008.08.015. Epub, 2008 Sep 4. PMID:18822302 doi:10.1016/j.mrfmmm.2008.08.015
59. ↑ Drost M, Zonneveld JB, van Hees S, Rasmussen LJ, Hofstra RM, de Wind N. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. Hum Mutat. 2012 Mar;33(3):488-94. doi: 10.1002/humu.22000. Epub 2011 Dec 29. PMID:22102614 doi:10.1002/humu.22000
60. ↑ Zahary MN, Kaur G, Abu Hassan MR, Singh H, Naik VR, Ankathil R. Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients. World J Gastroenterol. 2012 Feb 28;18(8):814-20. doi: 10.3748/wjg.v18.i8.814. PMID:22371642 doi:10.3748/wjg.v18.i8.814
61. ↑ Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MR, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics. 1994 Dec;24(3):516-26. PMID:7713503
62. ↑ Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P. Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem. 1998 Nov 27;273(48):32055-62. PMID:9822680
63. ↑ Blackwell LJ, Bjornson KP, Modrich P. DNA-dependent activation of the hMutSalpha ATPase. J Biol Chem. 1998 Nov 27;273(48):32049-54. PMID:9822679
64. ↑ Iaccarino I, Marra G, Palombo F, Jiricny J. hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha. EMBO J. 1998 May 1;17(9):2677-86. PMID:9564049 doi:10.1093/emboj/17.9.2677
65. ↑ Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R. hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol Cell. 1999 Feb;3(2):255-61. PMID:10078208
66. ↑ Gradia S, Acharya S, Fishel R. The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. J Biol Chem. 2000 Feb 11;275(6):3922-30. PMID:10660545
67. ↑ Yang Q, Zhang R, Wang XW, Linke SP, Sengupta S, Hickson ID, Pedrazzi G, Perrera C, Stagljar I, Littman SJ, Modrich P, Harris CC. The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. Oncogene. 2004 May 6;23(21):3749-56. PMID:15064730 doi:10.1038/sj.onc.1207462
68. ↑ Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P. Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem. 1998 Nov 27;273(48):32055-62. PMID:9822680
69. ↑ Blackwell LJ, Bjornson KP, Modrich P. DNA-dependent activation of the hMutSalpha ATPase. J Biol Chem. 1998 Nov 27;273(48):32049-54. PMID:9822679
70. ↑ Iaccarino I, Marra G, Palombo F, Jiricny J. hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha. EMBO J. 1998 May 1;17(9):2677-86. PMID:9564049 doi:10.1093/emboj/17.9.2677
71. ↑ Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R. hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol Cell. 1999 Feb;3(2):255-61. PMID:10078208
72. ↑ Gradia S, Acharya S, Fishel R. The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. J Biol Chem. 2000 Feb 11;275(6):3922-30. PMID:10660545
73. ↑ Yang Q, Zhang R, Wang XW, Linke SP, Sengupta S, Hickson ID, Pedrazzi G, Perrera C, Stagljar I, Littman SJ, Modrich P, Harris CC. The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. Oncogene. 2004 May 6;23(21):3749-56. PMID:15064730 doi:10.1038/sj.onc.1207462
74. ↑ Seifert M, Scherer SJ, Edelmann W, Bohm M, Meineke V, Lobrich M, Tilgen W, Reichrath J. The DNA-mismatch repair enzyme hMSH2 modulates UV-B-induced cell cycle arrest and apoptosis in melanoma cells. J Invest Dermatol. 2008 Jan;128(1):203-13. Epub 2007 Jul 5. PMID:17611581 doi:10.1038/sj.jid.5700941
75. ↑ Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS. Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell. 2007 May 25;26(4):579-92. PMID:17531815 doi:10.1016/j.molcel.2007.04.018