MutL Homolog 1 (MLH1)

COCA2; FCC2; HNPCC; HNPCC2; hMLH1; DNA mismatch repair protein Mlh1

SPN	O024
HGNC	7127
MGI	101938
PubMed	18712731
RGD	620937
UniProt	P40692
Wiki	MLH1

MLH1 was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). It is a human homolog of the E. coli DNA mismatch repair gene mutL, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Alternatively spliced transcript variants encoding different isoforms have been described, but their full-length natures have not been determined. The level of expression varied among different samples. All isoforms were found in 43 to 100% of the mononuclear blood cell samples, as well as in other tissues. The authors cautioned that knowledge of existence of multiple alternative splicing events not caused by genomic DNA changes is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis.

Reference

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Nature 368:258-261(1994) [PubMed] [Europe PMC] [Abstract]

"Mutation of a mutL homolog in hereditary colon cancer."
Science 263:1625-1629(1994) [PubMed] [Europe PMC] [Abstract]

"Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations."
Cancer Res. 55:242-248(1995) [PubMed] [Europe PMC] [Abstract]

"Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC)."
Hum. Mol. Genet. 4:237-242(1995) [PubMed] [Europe PMC] [Abstract]

"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]

"The DNA sequence, annotation and analysis of human chromosome 3."
Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

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Genes Dev. 14:927-939(2000) [PubMed] [Europe PMC] [Abstract]

"MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1."
Proc. Natl. Acad. Sci. U.S.A. 96:3969-3974(1999) [PubMed] [Europe PMC] [Abstract]

"The interaction of DNA mismatch repair proteins with human exonuclease I."
J. Biol. Chem. 276:33011-33018(2001) [PubMed] [Europe PMC] [Abstract]

"HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes."
Oncogene 20:3590-3595(2001) [PubMed] [Europe PMC] [Abstract]

"Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome."
Cancer Res. 62:6026-6030(2002) [PubMed] [Europe PMC] [Abstract]

"Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA."
Oncogene 23:1457-1468(2004) [PubMed] [Europe PMC] [Abstract]

"The genetic basis of Muir-Torre syndrome includes the hMLH1 locus."
Am. J. Hum. Genet. 59:736-739(1996) [PubMed] [Europe PMC] [Abstract]

"Endonucleolytic function of MutLalpha in human mismatch repair."
Cell 126:297-308(2006) [PubMed] [Europe PMC] [Abstract]

"Direct visualization of asymmetric adenine nucleotide-induced conformational changes in MutL alpha."
Mol. Cell 29:112-121(2008) [PubMed] [Europe PMC] [Abstract]

"Human mismatch repair: reconstitution of a nick-directed bidirectional reaction."
J. Biol. Chem. 280:39752-39761(2005) [PubMed] [Europe PMC] [Abstract]

"MutLalpha: at the cutting edge of mismatch repair."
Cell 126:239-241(2006) [PubMed] [Europe PMC] [Abstract]

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"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]

"A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair."
Mol. Cell 39:36-47(2010) [PubMed] [Europe PMC] [Abstract]

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N. Engl. J. Med. 332:839-847(1995) [PubMed] [Europe PMC] [Abstract]

"Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16."
Am. J. Hum. Genet. 58:300-307(1996) [PubMed] [Europe PMC] [Abstract]

"CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations."
Hum. Genet. 97:251-255(1996) [PubMed] [Europe PMC] [Abstract]

"Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer."
Hum. Mol. Genet. 5:1245-1252(1996) [PubMed] [Europe PMC] [Abstract]

"Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer."
J. Natl. Cancer Inst. 88:1317-1319(1996) [PubMed] [Europe PMC] [Abstract]

"Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in sporadic endometrial carcinomas with microsatellite instability."
Jpn. J. Cancer Res. 87:141-145(1996) [PubMed] [Europe PMC] [Abstract]

"Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations."
Am. J. Hum. Genet. 61:329-335(1997) [PubMed] [Europe PMC] [Abstract]

"Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer."
Genes Chromosomes Cancer 18:8-18(1997) [PubMed] [Europe PMC] [Abstract]

"MSH2 and MLH1 mutations in sporadic replication error-positive colorectal carcinoma as assessed by two-dimensional DNA electrophoresis."
Genes Chromosomes Cancer 18:269-278(1997) [PubMed] [Europe PMC] [Abstract]

"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 19:135-142(1997) [PubMed] [Europe PMC] [Abstract]

"Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria."
Hum. Genet. 99:219-224(1997) [PubMed] [Europe PMC] [Abstract]

"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. 100:362-364(1997) [PubMed] [Europe PMC] [Abstract]

"Mutational analysis of the hMLH1 gene using an automated two-dimensional DNA typing system."
Hum. Mutat. 9:164-171(1997) [PubMed] [Europe PMC] [Abstract]

"Molecular basis of HNPCC: mutations of MMR genes."
Hum. Mutat. 10:89-99(1997) [PubMed] [Europe PMC] [Abstract]

"Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes."
Hum. Mutat. 10:241-244(1997) [PubMed] [Europe PMC] [Abstract]

"Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families."
Int. J. Cancer 73:831-836(1997) [PubMed] [Europe PMC] [Abstract]

"Germline HNPCC gene variants have little influence on the risk for sporadic colorectal cancer."
J. Med. Genet. 34:39-42(1997) [PubMed] [Europe PMC] [Abstract]

"A human compound heterozygote for two MLH1 missense mutations."
Nat. Genet. 17:135-136(1997) [PubMed] [Europe PMC] [Abstract]

"Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls."
Am. J. Hum. Genet. 63:749-759(1998) [PubMed] [Europe PMC] [Abstract]

"DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLH1) in 34 Swedish families with colorectal cancer."
Clin. Genet. 53:131-135(1998) [PubMed] [Europe PMC] [Abstract]

"Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer."
Dis. Colon Rectum 41:434-440(1998) [PubMed] [Europe PMC] [Abstract]

"A novel missense mutation in the DNA mismatch repair gene hMLH1 present among East Asians but not among Europeans."
Hum. Hered. 48:87-91(1998) [PubMed] [Europe PMC] [Abstract]

"Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability."
Hum. Mutat. 12:73-73(1998) [PubMed] [Europe PMC] [Abstract]

"hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds."
Hum. Mutat. 12:216-217(1998) [PubMed] [Europe PMC] [Abstract]

"Hereditary nonpolyposis colorectal cancer: identification of novel germline mutations in two kindreds not fulfilling the Amsterdam criteria."
Hum. Mutat. 12:433-433(1998) [PubMed] [Europe PMC] [Abstract]

"Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer."
Int. J. Cancer 78:680-684(1998) [PubMed] [Europe PMC] [Abstract]

"Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer."
Cancer 85:2512-2518(1999) [PubMed] [Europe PMC] [Abstract]

"Neurofibromatosis and early onset of cancers in hMLH1-deficient children."
Cancer Res. 59:294-297(1999) [PubMed] [Europe PMC] [Abstract]

"Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2."
Eur. J. Hum. Genet. 7:778-782(1999) [PubMed] [Europe PMC] [Abstract]

"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 44:839-843(1999) [PubMed] [Europe PMC] [Abstract]

"Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer."
Hum. Genet. 105:79-85(1999) [PubMed] [Europe PMC] [Abstract]

"Missense mutations in hMLH1 associated with colorectal cancer."
Hum. Genet. 105:437-441(1999) [PubMed] [Europe PMC] [Abstract]

"Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer."
JAMA 281:2316-2320(1999) [PubMed] [Europe PMC] [Abstract]

"Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer."
J. Natl. Cancer Inst. 91:1221-1226(1999) [PubMed] [Europe PMC] [Abstract]

"Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds."
Biochem. Biophys. Res. Commun. 271:120-129(2000) [PubMed] [Europe PMC] [Abstract]

"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. 8:49-53(2000) [PubMed] [Europe PMC] [Abstract]

"Mutational germline analysis of hMSH2 and hMLH1 genes in early onset colorectal cancer patients."
J. Med. Genet. 37:E7-E7(2000) [PubMed] [Europe PMC] [Abstract]

Erratum
J. Med. Genet. 40:472-472(2003)

"hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer."
Cancer Detect. Prev. 25:503-510(2001) [PubMed] [Europe PMC] [Abstract]

"Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma in situ of the breast."
Cancer Lett. 167:171-174(2001) [PubMed] [Europe PMC] [Abstract]

"Extensive somatic microsatellite mutations in normal human tissue."
Cancer Res. 61:4541-4544(2001) [PubMed] [Europe PMC] [Abstract]

"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. 6:473-482(2001) [PubMed] [Europe PMC] [Abstract]

"Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae."
Hum. Mol. Genet. 10:1889-1900(2001) [PubMed] [Europe PMC] [Abstract]

"Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes."
Hum. Mutat. 17:52-60(2001) [PubMed] [Europe PMC] [Abstract]

"Eight novel germline MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer families from Spain."
Hum. Mutat. 18:549-549(2001) [PubMed] [Europe PMC] [Abstract]

"hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer."
Ann. Surg. Oncol. 9:555-561(2002) [PubMed] [Europe PMC] [Abstract]

"Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach."
Br. J. Cancer 87:892-897(2002) [PubMed] [Europe PMC] [Abstract]

"Microsatellite instability and mutation analysis of candidate genes in unselected Sardinian patients with endometrial carcinoma."
Cancer 94:3157-3168(2002) [PubMed] [Europe PMC] [Abstract]

"Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system."
Gastroenterology 122:211-219(2002) [PubMed] [Europe PMC] [Abstract]

"Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing."
Gut 50:405-412(2002) [PubMed] [Europe PMC] [Abstract]

"Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer."
Genes Chromosomes Cancer 33:160-167(2002) [PubMed] [Europe PMC] [Abstract]

"Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer."
Hum. Mutat. 19:82-82(2002) [PubMed] [Europe PMC] [Abstract]

"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. 128:403-411(2002) [PubMed] [Europe PMC] [Abstract]

"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. 20:1203-1208(2002) [PubMed] [Europe PMC] [Abstract]

"Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States."
J. Med. Genet. 39:E65-E65(2002) [PubMed] [Europe PMC] [Abstract]

"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. 72:1088-1100(2003) [PubMed] [Europe PMC] [Abstract]

"Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases."
Ann. Oncol. 14:1530-1536(2003) [PubMed] [Europe PMC] [Abstract]

"Identification of six novel MSH2 and MLH1 germline mutations in HNPCC."
Hum. Mutat. 21:445-446(2003) [PubMed] [Europe PMC] [Abstract]

"Genetic analysis of familial colorectal cancer in Israeli Arabs."
Hum. Mutat. 21:446-447(2003) [PubMed] [Europe PMC] [Abstract]

"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. 22:428-433(2003) [PubMed] [Europe PMC] [Abstract]

"HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1."
Genes Chromosomes Cancer 40:261-265(2004) [PubMed] [Europe PMC] [Abstract]

"Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families."
Hum. Mutat. 24:351-351(2004) [PubMed] [Europe PMC] [Abstract]

Erratum
Hum. Mutat. 25:224-224(2005)

"Ten novel MSH2 and MLH1 germline mutations in families with HNPCC."
Hum. Mutat. 24:351-352(2004) [PubMed] [Europe PMC] [Abstract]

"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 109:370-376(2004) [PubMed] [Europe PMC] [Abstract]

Erratum
Int. J. Cancer 115:1011-1011(2005)

"Germline epimutation of MLH1 in individuals with multiple cancers."
Nat. Genet. 36:497-501(2004) [PubMed] [Europe PMC] [Abstract]

"The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer."
Nat. Genet. 36:694-699(2004) [PubMed] [Europe PMC] [Abstract]

"Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1."
Gastroenterology 129:537-549(2005) [PubMed] [Europe PMC] [Abstract]

"Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study)."
Clin. Genet. 69:40-47(2006) [PubMed] [Europe PMC] [Abstract]

"Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies."
Cancer 109:2349-2356(2007) [PubMed] [Europe PMC] [Abstract]

"Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays."
Cancer Res. 67:4595-4604(2007) [PubMed] [Europe PMC] [Abstract]

"Inheritance of a cancer-associated MLH1 germ-line epimutation."
N. Engl. J. Med. 356:697-705(2007) [PubMed] [Europe PMC] [Abstract]

"Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer."
Hum. Mutat. 29:367-374(2008) [PubMed] [Europe PMC] [Abstract]

"A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects."
Hum. Mutat. 29:1412-1424(2008) [PubMed] [Europe PMC] [Abstract]