MLH1 (human mutL homolog 1)

2005-02-01   Enrico Domingo , Simo Schwartz Jr 

Oncologia Molecular i Envelliment, Centre dInvestigacions en Bioqumica i Biologia Molecular (CIBBIM) Hospital Universitari Vall dHebron Passeig Vall dHebron 119-129 Barcelona 08035, Catalonia, Spain

Identity

HGNC
LOCATION
3p22.2
LOCUSID
ALIAS
COCA2,FCC2,HNPCC,HNPCC2,MMRCS1,hMLH1
FUSION GENES

DNA/RNA

Atlas Image
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

Proteins

Atlas Image
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
155635102005Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.Alazzouzi H et al
87518761996The genetic basis of Muir-Torre syndrome includes the hMLH1 locus.Bapat B et al
81458271994Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.Bronner CE et al
76963681995Microsatellite instability in inherited and sporadic neoplasms.Eshleman JR et al
119008752002DNA mismatch repair defects: role in colorectal carcinogenesis.Jacob S et al
98922011999hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability.Leung SY et al
119206792002DNA mismatch repair and mutation avoidance pathways.Marti TM et al
124197612002Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.Mitchell RJ et al
96717411998Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.Veigl ML et al

Other Information

Locus ID:

NCBI: 4292
MIM: 120436
HGNC: 7127
Ensembl: ENSG00000076242

Variants:

dbSNP: 4292
ClinVar: 4292
TCGA: ENSG00000076242
COSMIC: MLH1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000076242ENST00000231790P40692
ENSG00000076242ENST00000413212H0Y5U4
ENSG00000076242ENST00000413740H0Y806
ENSG00000076242ENST00000429117C9JZ54
ENSG00000076242ENST00000432299E9PF25
ENSG00000076242ENST00000435176P40692
ENSG00000076242ENST00000441265E7EUC9
ENSG00000076242ENST00000447829H0Y5L7
ENSG00000076242ENST00000450420H0Y4N0
ENSG00000076242ENST00000454028F2Z298
ENSG00000076242ENST00000455445P40692
ENSG00000076242ENST00000455445A0A024R2S9
ENSG00000076242ENST00000456676H0Y818
ENSG00000076242ENST00000457004F2Z298
ENSG00000076242ENST00000458009H0Y793
ENSG00000076242ENST00000458205P40692
ENSG00000076242ENST00000458205A0A024R2S9
ENSG00000076242ENST00000536378P40692
ENSG00000076242ENST00000536378A0A024R2S9
ENSG00000076242ENST00000539477P40692
ENSG00000076242ENST00000539477A0A024R2S9
ENSG00000076242ENST00000616768A0A087WX20
ENSG00000076242ENST00000674019A0A024R2S9

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Mismatch repairKEGGko03430
Colorectal cancerKEGGko05210
Endometrial cancerKEGGko05213
Mismatch repairKEGGhsa03430
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Endometrial cancerKEGGhsa05213
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
DNA RepairREACTOMER-HSA-73894
Mismatch RepairREACTOMER-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)REACTOMER-HSA-5358565
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)REACTOMER-HSA-5358606
TP53 Regulates Transcription of DNA Repair GenesREACTOMER-HSA-6796648
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443761Colorectal Neoplasms, Hereditary NonpolyposisDiseaseLiterature, MultilinkAnnotationassociated23788249

References

Pubmed IDYearTitleCitations
216426822011Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.198
175919292007Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.156
168853852006Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.149
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
150647642004Germline epimutation of MLH1 in individuals with multiple cancers.113
168074122006Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.108
196223572009Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome.101
191651972009Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.97
223319442012Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.95

Citation

Enrico Domingo ; Simo Schwartz Jr

MLH1 (human mutL homolog 1)

Atlas Genet Cytogenet Oncol Haematol. 2005-02-01

Online version: http://atlasgeneticsoncology.org/gene/149/mlh1