4p7a

Structural highlights

Disease

MLH1_HUMAN Muir-Torre syndrome;Hereditary nonpolyposis colon cancer. Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:609310. 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, and accounts for 15% of all colon cancers. 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.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [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]} Defects in MLH1 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.^{[59] [60] [61]} Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.^[62] Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.^[63] Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089. Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.

Function

MLH1_HUMAN Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.^{[64] [65]}

See Also

• DNA mismatch repair protein 3D structures

References

1. ↑ Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R. The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem. 2001 Aug 31;276(35):33011-8. Epub 2001 Jun 26. PMID:11427529 doi:10.1074/jbc.M102670200
2. ↑ Han HJ, Maruyama M, Baba S, Park JG, Nakamura Y. Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC) Hum Mol Genet. 1995 Feb;4(2):237-42. PMID:7757073
3. ↑ Jager AC, Rasmussen M, Bisgaard HC, Singh KK, Nielsen FC, Rasmussen LJ. HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. Oncogene. 2001 Jun 14;20(27):3590-5. PMID:11429708 doi:10.1038/sj.onc.1204467
4. ↑ Wijnen J, Khan PM, Vasen H, Menko F, van der Klift H, van den Broek M, van Leeuwen-Cornelisse I, Nagengast F, Meijers-Heijboer EJ, Lindhout D, Griffioen G, Cats A, Kleibeuker J, Varesco L, Bertario L, Bisgaard ML, Mohr J, Kolodner R, Fodde R. Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. Am J Hum Genet. 1996 Feb;58(2):300-7. PMID:8571956
5. ↑ Maliaka YK, Chudina AP, Belev NF, Alday P, Bochkov NP, Buerstedde JM. CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. Hum Genet. 1996 Feb;97(2):251-5. PMID:8566964
6. ↑ 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
7. ↑ Han HJ, Yuan Y, Ku JL, Oh JH, Won YJ, Kang KJ, Kim KY, Kim S, Kim CY, Kim JP, Oh NG, Lee KH, Choe KJ, Nakamura Y, Park JG. Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst. 1996 Sep 18;88(18):1317-9. PMID:8797773
8. ↑ 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
9. ↑ Viel A, Genuardi M, Capozzi E, Leonardi F, Bellacosa A, Paravatou-Petsotas M, Pomponi MG, Fornasarig M, Percesepe A, Roncucci L, Tamassia MG, Benatti P, Ponz de Leon M, Valenti A, Covino M, Anti M, Foletto M, Boiocchi M, Neri G. Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer. Genes Chromosomes Cancer. 1997 Jan;18(1):8-18. PMID:8993976
10. ↑ Pensotti V, Radice P, Presciuttini S, Calistri D, Gazzoli I, Grimalt Perez A, Mondini P, Buonsanti G, Sala P, Rossetti C, Ranzani GN, Bertario L, Pierotti MA. Mean age of tumor onset in hereditary nonpolyposis colorectal cancer (HNPCC) families correlates with the presence of mutations in DNA mismatch repair genes. Genes Chromosomes Cancer. 1997 Jul;19(3):135-42. PMID:9218993
11. ↑ 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
12. ↑ Wang Y, Friedl W, Lamberti C, Ruelfs C, Kruse R, Propping P. Hereditary nonpolyposis colorectal cancer: causative role of a germline missense mutation in the hMLH1 gene confirmed by the independent occurrence of the same somatic mutation in tumour tissue. Hum Genet. 1997 Sep;100(3-4):362-4. PMID:9272156
13. ↑ Sasaki S, Tokino T, Miyatsu T, Muto T, Nakamura Y. Mutational analysis of the hMLH1 gene using an automated two-dimensional DNA typing system. Hum Mutat. 1997;9(2):164-71. PMID:9067757 doi:<164::AID-HUMU9>3.0.CO;2-9 10.1002/(SICI)1098-1004(1997)9:2<164::AID-HUMU9>3.0.CO;2-9
14. ↑ 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-#
15. ↑ Wang Q, Desseigne F, Lasset C, Saurin JC, Navarro C, Yagci T, Keser I, Bagci H, Luleci G, Gelen T, Chayvialle JA, Puisieux A, Ozturk M. Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families. Int J Cancer. 1997 Dec 10;73(6):831-6. PMID:9399661
16. ↑ Hackman P, Tannergard P, Osei-Mensa S, Chen J, Kane MF, Kolodner R, Lambert B, Hellgren D, Lindblom A. A human compound heterozygote for two MLH1 missense mutations. Nat Genet. 1997 Oct;17(2):135-6. PMID:9326924 doi:10.1038/ng1097-135
17. ↑ 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
18. ↑ 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
19. ↑ Klaus K, Herfarth F, Ogunbiyi OA, Moley JF, Kodner IJ, Wells SA Jr, Goodfellow PJ. Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability. Mutations in brief no. 157. Online. Hum Mutat. 1998;12(1):73. PMID:10627141 doi:<73::AID-HUMU20>3.0.CO;2-F 10.1002/(SICI)1098-1004(1998)12:1<73::AID-HUMU20>3.0.CO;2-F
20. ↑ Panariello L, Scarano MI, de Rosa M, Capasso L, Renda A, Riegler G, Rossi GB, Salvatore F, Izzo P. hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds. Mutations in brief no. 182. Online. Hum Mutat. 1998;12(3):216-7. PMID:10660333
21. ↑ Quaresima B, Grandinetti C, Baudi F, Tassone P, Barbieri V, Conforti S, Avvedimento EV, Costanzo F, Venuta S. Hereditary nonpolyposis coloretal cancer: identification of novel germline mutations in two kindreds not fulfulling the Amsterdam criteria. Mutations in brief no. 203. Online. Hum Mutat. 1998;12(6):433. PMID:10671064 doi:<433::AID-HUMU13>3.0.CO;2-J 10.1002/(SICI)1098-1004(1998)12:6<433::AID-HUMU13>3.0.CO;2-J
22. ↑ Hutter P, Couturier A, Membrez V, Joris F, Sappino AP, Chappuis PO. Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer. Int J Cancer. 1998 Dec 9;78(6):680-4. PMID:9833759
23. ↑ 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
24. ↑ Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999 Jan 15;59(2):294-7. PMID:9927034
25. ↑ Lamberti C, Kruse R, Ruelfs C, Caspari R, Wang Y, Jungck M, Mathiak M, Malayeri HR, Friedl W, Sauerbruch T, Propping P. Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut. 1999 Jun;44(6):839-43. PMID:10323887
26. ↑ 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
27. ↑ Liu T, Tannergard P, Hackman P, Rubio C, Kressner U, Lindmark G, Hellgren D, Lambert B, Lindblom A. Missense mutations in hMLH1 associated with colorectal cancer. Hum Genet. 1999 Nov;105(5):437-41. PMID:10598809
28. ↑ 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
29. ↑ Chan TL, Yuen ST, Chung LP, Ho JW, Kwan KY, Chan AS, Ho JC, Leung SY, Wyllie AH. Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. J Natl Cancer Inst. 1999 Jul 21;91(14):1221-6. PMID:10413423
30. ↑ 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
31. ↑ Fidalgo P, Almeida MR, West S, Gaspar C, Maia L, Wijnen J, Albuquerque C, Curtis A, Cravo M, Fodde R, Leitao CN, Burn J. Detection of mutations in mismatch repair genes in Portuguese families with hereditary non-polyposis colorectal cancer (HNPCC) by a multi-method approach. Eur J Hum Genet. 2000 Jan;8(1):49-53. PMID:10713887 doi:10.1038/sj.ejhg.5200393
32. ↑ Montera M, Resta N, Simone C, Guanti G, Marchese C, Civitelli S, Mancini A, Pozzi S, De Salvo L, Bruzzone D, Donadini A, Romio L, Mareni C. Mutational germline analysis of hMSH2 and hMLH1 genes in early onset colorectal cancer patients. J Med Genet. 2000 Jul;37(7):E7. PMID:10882759
33. ↑ 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
34. ↑ 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
35. ↑ Jakubowska A, Gorski B, Kurzawski G, Debniak T, Hadaczek P, Cybulski C, Kladny J, Oszurek O, Scott RJ, Lubinski J. Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes. Hum Mutat. 2001;17(1):52-60. PMID:11139242 doi:<52::AID-HUMU6>3.0.CO;2-E 10.1002/1098-1004(2001)17:1<52::AID-HUMU6>3.0.CO;2-E
36. ↑ Godino J, de La Hoya M, Diaz-Rubio E, Benito M, Caldes T. Eight novel germline MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer families from Spain. Hum Mutat. 2001 Dec;18(6):549. PMID:11748856 doi:10.1002/humu.1240
37. ↑ Rossi BM, Lopes A, Oliveira Ferreira F, Nakagawa WT, Napoli Ferreira CC, Casali Da Rocha JC, Simpson CC, Simpson AJ. hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer. Ann Surg Oncol. 2002 Jul;9(6):555-61. PMID:12095971
38. ↑ 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
39. ↑ Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology. 2002 Jan;122(1):211-9. PMID:11781295
40. ↑ Cravo M, Afonso AJ, Lage P, Albuquerque C, Maia L, Lacerda C, Fidalgo P, Chaves P, Cruz C, Nobre-Leitao C. Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing. Gut. 2002 Mar;50(3):405-12. PMID:11839723
41. ↑ Nystrom-Lahti M, Perrera C, Raschle M, Panyushkina-Seiler E, Marra G, Curci A, Quaresima B, Costanzo F, D'Urso M, Venuta S, Jiricny J. Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes Chromosomes Cancer. 2002 Feb;33(2):160-7. PMID:11793442
42. ↑ Kruger S, Plaschke J, Pistorius S, Jeske B, Haas S, Kramer H, Hinterseher I, Bier A, Kreuz FR, Theissig F, Saeger HD, Schackert HK. Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer. Hum Mutat. 2002 Jan;19(1):82. PMID:11754112 doi:10.1002/humu.9004
43. ↑ 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
44. ↑ 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
45. ↑ 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
46. ↑ 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
47. ↑ Kruger S, Plaschke J, Jeske B, Gorgens H, Pistorius SR, Bier A, Kreuz FR, Theissig F, Aust DE, Saeger HD, Schackert HK. Identification of six novel MSH2 and MLH1 germline mutations in HNPCC. Hum Mutat. 2003 Apr;21(4):445-6. PMID:12655562 doi:10.1002/humu.9121
48. ↑ 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
49. ↑ Raevaara TE, Gerdes AM, Lonnqvist KE, Tybjaerg-Hansen A, Abdel-Rahman WM, Kariola R, Peltomaki P, Nystrom-Lahti M. HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Genes Chromosomes Cancer. 2004 Jul;40(3):261-5. PMID:15139004 doi:10.1002/gcc.20040
50. ↑ 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
51. ↑ Kruger S, Bier A, Plaschke J, Hohl R, Aust DE, Kreuz FR, Pistorius SR, Saeger HD, Rothhammer V, Al-Taie O, Schackert HK. Ten novel MSH2 and MLH1 germline mutations in families with HNPCC. Hum Mutat. 2004 Oct;24(4):351-2. PMID:15365996 doi:10.1002/humu.9278
52. ↑ Cederquist K, Emanuelsson M, Goransson I, Holinski-Feder E, Muller-Koch Y, Golovleva I, Gronberg H. Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. Int J Cancer. 2004 Apr 10;109(3):370-6. PMID:14961575 doi:10.1002/ijc.11718
53. ↑ Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet. 2004 May;36(5):497-501. Epub 2004 Apr 4. PMID:15064764 doi:10.1038/ng1342
54. ↑ Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lonnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes AM, Peltomaki P, Kohonen-Ccorish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, Nystrom M. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology. 2005 Aug;129(2):537-49. PMID:16083711 doi:10.1016/j.gastro.2005.06.005
55. ↑ 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
56. ↑ Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007 May 15;67(10):4595-604. PMID:17510385 doi:67/10/4595
57. ↑ Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ, Ward RL. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med. 2007 Feb 15;356(7):697-705. PMID:17301300 doi:10.1056/NEJMoa064522
58. ↑ 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
59. ↑ Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R. The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem. 2001 Aug 31;276(35):33011-8. Epub 2001 Jun 26. PMID:11427529 doi:10.1074/jbc.M102670200
60. ↑ Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al.. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839-47. PMID:7661930
61. ↑ Poley JW, Wagner A, Hoogmans MM, Menko FH, Tops C, Kros JM, Reddingius RE, Meijers-Heijboer H, Kuipers EJ, Dinjens WN. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer. 2007 Jun 1;109(11):2349-56. PMID:17440981 doi:10.1002/cncr.22697
62. ↑ Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S. The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet. 1996 Sep;59(3):736-9. PMID:8751876
63. ↑ Stone JG, Coleman G, Gusterson B, Marossy A, Lakhani SR, Ward A, Nash A, McKinna A, A'Hern R, Stratton MR, Houlston RS. Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma in situ of the breast. Cancer Lett. 2001 Jun 26;167(2):171-4. PMID:11369138
64. ↑ Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006 Jul 28;126(2):297-308. PMID:16873062 doi:S0092-8674(06)00812-9
65. ↑ Sacho EJ, Kadyrov FA, Modrich P, Kunkel TA, Erie DA. Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha. Mol Cell. 2008 Jan 18;29(1):112-21. PMID:18206974 doi:S1097-2765(07)00817-9
66. ↑ Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):981-5. doi:, 10.1107/S2053230X15010183. Epub 2015 Jul 28. PMID:26249686 doi:http://dx.doi.org/10.1107/S2053230X15010183