MLH1 (human mutL homolog 1)

Identity

Other names	COCA2
	FCC2
	hMLH1
	HNPCC2
HGNC	MLH1
Location	3p21.3
Local_order	Between the KIAA0342 and LRRFIP2 genes

DNA/RNA

	Diagram of the MLH1 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.
Description	The MLH1 gene is composed of 19 exons spanning in a region of 57360 bp.
Transcription	The transcribed mRNA has 2524 bp

Protein

	Diagram of the MLH1 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the ATPase domain, the MutS homologs interaction domain and the PMS2/MLH3/PMS1 interaction domain; C: Carboxyl-terminal; N: Amino-terminal

Description	Aminoacids: 756. Molecular Weight: 84.6 kDa. MLH1 is a protein involved in the mismatch repair process after DNA replication. It contains an ATPase domain and two interaction domains, one for MutS homologs (MSH2, MSH3, MSH6) and the other for PMS2, MLH3 or PMS1.
Localisation	Nuclear
Function	MLH1 has no known enzymatic activity. MLH1 forms a heterodimer with PMS2 known as MutLa, although it can also bind to PMS1 or MLH3. This heterodimeric complex binds to the heteroduplexes MutSa (composed of MSH2 and MSH6) or MutSb (composed of MSH2 and MSH3), which recognize DNA lesions. The heterodimer formed by MLH1 is responsible for the recruitment of the proteins needed for the excision and repair synthesis.
Homology	MLH1 is homologue to the bacterial MutL gene, specially in the N-terminal region, and MLH1 homologues are also present in eukaryotes (for example in Mus musculus, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisae)

Mutations

Germinal

There are over 300 MLH1 germline mutations described all along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). This mutations are not present in any particular hotspot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. There are also founding mutations which account for a high proportion of the HNPCC tumours in some specific populations (for example there are two Finnish mutations that delete the exons 16 or 6). Some germline genetic changes have also been described in both exons and introns as non pathogenic.

Somatic

There are described some sporadic mismatch repair deficiency cases (sporadic MSI) with somatic MLH1 mutations, although most of them have MLH1 promoter hypermetilation.

Implicated in

Entity	HNPCC (Hereditary Non Polyposis Colorectal Cancer)
Disease	Predisposition to develop cancer, preferentially colorectal, but also in endometrium, ovary, urinary tract, stomach, small bowel, biliary tract and brain.
Oncogenesis	MLH1 mutations in HNPCC account for about 25% of the total cases approximately. This mutations are inherited in one allele and later the other allele is lost by LOH. This leads to mismatch repair deficiency in this patients, which is the cause of the accumulation of mutations along the genome, causing microsatellite instability (MSI) and promoting tumorigenesis. It has been suggested that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.
Entity	MSI (MicroSatellite Instability)
Note	Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.
Disease	This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and with lower incidence in some other tissues.
Prognosis	MSI tumours have better prognosis than the MicroSatellite Stable (MSS).
Oncogenesis	Sporadic MSI cases are mostly due to a biallelic hypermetilation of the MLH1 promotor and therefore lack of MLH1 protein expression. Few sporadic cases and about 25% of the HNPCC are due to different mutations in MLH1. These mutations are germline in HNPCC.
Entity	Muir-Torre syndrome
Disease	Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy.
Oncogenesis	Inherited MLH1 mutations can cause Muir-Torre syndrome (although MSH2 mutations are more present).

External links

	Nomenclature
HGNC	MLH1   7127
Entrez_Gene	MLH1  4292  mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
	Cards
Atlas	MLH1ID149ch3p21
GeneCards	MLH1
Ensembl	MLH1 [Search_View]   ENSG00000076242 [Gene_View]
Genatlas	MLH1
GeneLynx	MLH1
eGenome	MLH1
euGene	4292
	Genomic and cartography
GoldenPath	MLH1  -  3p21.3   chr3:37009983-37067341 +  3p22.3   [Description]    (hg18-Mar_2006)
Ensembl	MLH1 - 3p22.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MLH1
	Gene and transcription
Genbank	AB209848 [ ENTREZ ]
Genbank	AF001359 [ ENTREZ ]
Genbank	AK222810 [ ENTREZ ]
Genbank	AK295359 [ ENTREZ ]
Genbank	AK298324 [ ENTREZ ]
RefSeq	NM_000249 [ SRS ]    NM_000249 [ ENTREZ ]
RefSeq	AC_000046 [ SRS ]    AC_000046 [ ENTREZ ]
RefSeq	AC_000135 [ SRS ]    AC_000135 [ ENTREZ ]
RefSeq	NC_000003 [ SRS ]    NC_000003 [ ENTREZ ]
RefSeq	NG_007109 [ SRS ]    NG_007109 [ ENTREZ ]
RefSeq	NT_022517 [ SRS ]    NT_022517 [ ENTREZ ]
RefSeq	NW_001838877 [ SRS ]    NW_001838877 [ ENTREZ ]
RefSeq	NW_921651 [ SRS ]    NW_921651 [ ENTREZ ]
AceView	MLH1 AceView - NCBI
Unigene	Hs.195364 [ SRS ]    Hs.195364 [ NCBI ]     HS195364 [ spliceNest ]
Fast-db	3785 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O00497 [ SRS]    O00497 [ EXPASY ]     O00497 [ INTERPRO ]     O00497 [ UNIPROT ]
CluSTr	O00497
Blocks	O00497
HPRD	00390
	Protein Interaction databases
DIP	O00497
IntAct	O00497
	Polymorphism : SNP, mutations, diseases
OMIM	114030;120436;158320;276300;609310    [ map ]
GENECLINICS	114030;120436;158320;276300;609310
SNP	MLH1 [dbSNP-NCBI]
SNP	NM_000249 [SNP-NCI]
SNP	MLH1 [GeneSNPs - Utah]  MLH1] [HGBASE - SRS]
HAPMAP	MLH1 [HAPMAP]
COSMIC	MLH1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	MLH1
	General knowledge
Family Browser	MLH1 [UCSC Family Browser]
SOURCE	NM_000249
SMD	Hs.195364
SAGE	Hs.195364
GO	single-stranded DNA binding [Amigo]  single-stranded DNA binding
GO	protein binding [Amigo]  protein binding
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	nucleus [Amigo]  nucleus
GO	mismatch repair [Amigo]  mismatch repair
GO	mismatch repair [Amigo]  mismatch repair
GO	mismatch repair [Amigo]  mismatch repair
GO	mismatched DNA binding [Amigo]  mismatched DNA binding
GO	guanine/thymine mispair binding [Amigo]  guanine/thymine mispair binding
GO	MutSalpha complex binding [Amigo]  MutSalpha complex binding
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
KEGG	Colorectal cancer
PubGene	MLH1
TreeFam	MLH1
CTD	4292 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	MLH1 Related clones (RZPD - Berlin)
	PubMed
PubMed	369 Pubmed reference(s) in LocusLink

Bibliography

Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.

Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A

Nature. 1994 ; 368 (6468) : 258-261.

PMID 8145827

Microsatellite instability in inherited and sporadic neoplasms.

Eshleman JR, Markowitz SD

Current opinion in oncology. 1995 ; 7 (1) : 83-89.

PMID 7696368

The genetic basis of Muir-Torre syndrome includes the hMLH1 locus.

Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S

American journal of human genetics. 1996 ; 59 (3) : 736-739.

PMID 8751876

Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.

Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD

Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (15) : 8698-8702.

PMID 9671741

hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability.

Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC

Cancer research. 1999 ; 59 (1) : 159-164.

PMID 9892201

DNA mismatch repair defects: role in colorectal carcinogenesis.

Jacob S, Praz F

Biochimie. 2002 ; 84 (1) : 27-47.

PMID 11900875

DNA mismatch repair and mutation avoidance pathways.

Marti TM, Kunz C, Fleck O

Journal of cellular physiology. 2002 ; 191 (1) : 28-41.

PMID 11920679

Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.

Mitchell RJ, Farrington SM, Dunlop MG, Campbell H

American journal of epidemiology. 2002 ; 156 (10) : 885-902.

PMID 12419761

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.

Alazzouzi H, Domingo E, Gonzˆ°lez S, Blanco I, Armengol M, Espˆ‚n E, Plaja A, Schwartz S, Capella G, Schwartz S Jr

Human molecular genetics. 2005 ; 14 (2) : 235-239.

PMID 15563510

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	02-2005	Enrico Domingo, Simo Schwartz Jr
		Oncologia Molecular i Envelliment, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM) Hospital Universitari Vall d'Hebron Passeig Vall d'Hebron 119-129 Barcelona 08035, Catalonia, Spain

Citation

This paper should be referenced as such :

Domingo E, Schwartz S Jr . MLH1 (human mutL homolog 1). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MLH1ID149ch3p21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:15:22 2008