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MLH1 (human mutL homolog 1)

Written2005-02Enrico Domingo, Simo Schwartz Jr
Oncologia Molecular i Envelliment, Centre d'Investigacions en Bioqumica i Biologia Molecular (CIBBIM) Hospital Universitari Vall d'Hebron Passeig Vall d'Hebron 119-129 Barcelona 08035, Catalonia, Spain

(Note : for Links provided by Atlas : click)

Identity

Other namesCOCA2
FCC2
hMLH1
HNPCC2
HGNC (Hugo) MLH1
LocusID (NCBI) 4292
Atlas_Id 149
Location 3p22.2  [Link to chromosome band 3p22]
Location_base_pair Starts at 37034841 and ends at 37092337 bp from pter ( according to hg19-Feb_2009)  [Mapping MLH1.png]
Local_order Between the KIAA0342 and LRRFIP2 genes
Fusion genes
(updated 2016)
GOLGA4 (3p22.2) / MLH1 (3p22.2)HMGA1 (6p21.31) / MLH1 (3p22.2)IRS2 (13q34) / MLH1 (3p22.2)
LRRFIP2 (3p22.2) / MLH1 (3p22.2)MALAT1 (11q13.1) / MLH1 (3p22.2)MLH1 (3p22.2) / ITGA9 (3p22.2)
MLH1 (3p22.2) / MLH1 (3p22.2)UBAP2 (9p13.3) / MLH1 (3p22.2)

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

Note
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).
  

Bibliography

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.
Alazzouzi H, Domingo E, Gonz´lez S, Blanco I, Armengol M, Espín E, Plaja A, Schwartz S, Capella G, Schwartz S Jr
Human molecular genetics. 2005 ; 14 (2) : 235-239.
PMID 15563510
 
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
 
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
 
DNA mismatch repair defects: role in colorectal carcinogenesis.
Jacob S, Praz F
Biochimie. 2002 ; 84 (1) : 27-47.
PMID 11900875
 
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 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
 
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
 

Citation

This paper should be referenced as such :
Domingo, E ; Schwartz, S Jr
MLH1 (human mutL homolog 1)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):120-122.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MLH1ID149ch3p21.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Nasal T cell lymphoma

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ]
  Breast tumors : an overview
Colon: Colorectal adenocarcinoma
Breast: Ductal carcinoma
Gastric Tumors: an overview
Head and Neck: Oral leukoplakia
Pancreatic tumors: an overview

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 4 ]
  Familial nervous system tumour syndromes Hereditary pancreatic cancer Hereditary non polyposis colorectal carcinoma (HNPCC Syndrome) Turcot syndrome

External links

Nomenclature
HGNC (Hugo)MLH1   7127
Cards
AtlasMLH1ID149ch3p21
Entrez_Gene (NCBI)MLH1  4292  mutL homolog 1
AliasesCOCA2; FCC2; HNPCC; HNPCC2; 
hMLH1
GeneCards (Weizmann)MLH1
Ensembl hg19 (Hinxton)ENSG00000076242 [Gene_View]  chr3:37034841-37092337 [Contig_View]  MLH1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000076242 [Gene_View]  chr3:37034841-37092337 [Contig_View]  MLH1 [Vega]
ICGC DataPortalENSG00000076242
TCGA cBioPortalMLH1
AceView (NCBI)MLH1
Genatlas (Paris)MLH1
WikiGenes4292
SOURCE (Princeton)MLH1
Genomic and cartography
GoldenPath hg19 (UCSC)MLH1  -     chr3:37034841-37092337 +  3p22.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MLH1  -     3p22.3   [Description]    (hg38-Dec_2013)
EnsemblMLH1 - 3p22.3 [CytoView hg19]  MLH1 - 3p22.3 [CytoView hg38]
Mapping of homologs : NCBIMLH1 [Mapview hg19]  MLH1 [Mapview hg38]
OMIM120436   158320   276300   609310   
Gene and transcription
Genbank (Entrez)AB209848 AF001359 AK222810 AK295359 AK298324
RefSeq transcript (Entrez)NM_000249 NM_001167617 NM_001167618 NM_001167619 NM_001258271 NM_001258273 NM_001258274
RefSeq genomic (Entrez)NC_000003 NC_018914 NG_007109 NT_022517 NW_004929309
Consensus coding sequences : CCDS (NCBI)MLH1
Cluster EST : UnigeneHs.195364 [ NCBI ]
CGAP (NCI)Hs.195364
Alternative Splicing GalleryENSG00000076242
Gene ExpressionMLH1 [ NCBI-GEO ]   MLH1 [ EBI - ARRAY_EXPRESS ]   MLH1 [ SEEK ]   MLH1 [ MEM ]
Gene Expression Viewer (FireBrowse)MLH1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4292
GTEX Portal (Tissue expression)MLH1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP40692 (Uniprot)
NextProtP40692  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP40692
Splice isoforms : SwissVarP40692 (Swissvar)
PhosPhoSitePlusP40692
Domaine pattern : Prosite (Expaxy)DNA_MISMATCH_REPAIR_1 (PS00058)   
Domains : Interpro (EBI)DNA_mismatch_repair_C    DNA_mismatch_repair_CS    DNA_mismatch_repair_fam    HATPase_C    Mlh1_C    Ribosomal_S5_D2-typ_fold    Ribosomal_S5_D2-typ_fold_subgr   
Domain families : Pfam (Sanger)DNA_mis_repair (PF01119)    Mlh1_C (PF16413)   
Domain families : Pfam (NCBI)pfam01119    pfam16413   
Domain families : Smart (EMBL)HATPase_c (SM00387)  
DMDM Disease mutations4292
Blocks (Seattle)MLH1
PDB (SRS)3RBN    4P7A   
PDB (PDBSum)3RBN    4P7A   
PDB (IMB)3RBN    4P7A   
PDB (RSDB)3RBN    4P7A   
Structural Biology KnowledgeBase3RBN    4P7A   
SCOP (Structural Classification of Proteins)3RBN    4P7A   
CATH (Classification of proteins structures)3RBN    4P7A   
SuperfamilyP40692
Human Protein AtlasENSG00000076242
Peptide AtlasP40692
HPRD00390
IPIIPI00029754   IPI00927925   IPI00792036   IPI01012620   IPI00783524   IPI01008784   IPI01009952   IPI00924431   IPI00816514   IPI00974070   IPI00816656   IPI00783152   IPI00927918   IPI00795011   IPI00927923   IPI00926530   IPI00742734   IPI00924824   IPI00783078   
Protein Interaction databases
DIP (DOE-UCLA)P40692
IntAct (EBI)P40692
FunCoupENSG00000076242
BioGRIDMLH1
STRING (EMBL)MLH1
ZODIACMLH1
Ontologies - Pathways
QuickGOP40692
Ontology : AmiGOnuclear-transcribed mRNA poly(A) tail shortening  resolution of meiotic recombination intermediates  synaptonemal complex  male germ cell nucleus  chromatin binding  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  chiasma  mismatch repair  mismatch repair  double-strand break repair via nonhomologous end joining  male meiosis chromosome segregation  synapsis  spermatogenesis  intrinsic apoptotic signaling pathway in response to DNA damage  membrane  female meiosis chromosome segregation  somatic hypermutation of immunoglobulin genes  ATPase activity  guanine/thymine mispair binding  MutLalpha complex  MutSalpha complex binding  meiotic metaphase I plate congression  meiotic telomere clustering  isotype switching  negative regulation of mitotic recombination  oogenesis  meiotic spindle midzone assembly  
Ontology : EGO-EBInuclear-transcribed mRNA poly(A) tail shortening  resolution of meiotic recombination intermediates  synaptonemal complex  male germ cell nucleus  chromatin binding  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  chiasma  mismatch repair  mismatch repair  double-strand break repair via nonhomologous end joining  male meiosis chromosome segregation  synapsis  spermatogenesis  intrinsic apoptotic signaling pathway in response to DNA damage  membrane  female meiosis chromosome segregation  somatic hypermutation of immunoglobulin genes  ATPase activity  guanine/thymine mispair binding  MutLalpha complex  MutSalpha complex binding  meiotic metaphase I plate congression  meiotic telomere clustering  isotype switching  negative regulation of mitotic recombination  oogenesis  meiotic spindle midzone assembly  
Pathways : KEGGMismatch repair    Fanconi anemia pathway    Pathways in cancer    Colorectal cancer    Endometrial cancer   
REACTOMEP40692 [protein]
REACTOME PathwaysR-HSA-912446 Meiotic recombination [pathway]
REACTOME PathwaysR-HSA-5358606 Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) [pathway]
REACTOME PathwaysR-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkMLH1
Wikipedia pathwaysMLH1
Orthology - Evolution
OrthoDB4292
GeneTree (enSembl)ENSG00000076242
Phylogenetic Trees/Animal Genes : TreeFamMLH1
Homologs : HomoloGeneMLH1
Homology/Alignments : Family Browser (UCSC)MLH1
Gene fusions - Rearrangements
Fusion : MitelmanGOLGA4/MLH1 [3p22.2/3p22.2]  [t(3;3)(p22;p22)]  
Fusion: TCGAGOLGA4 3p22.2 MLH1 3p22.2 BRCA PRAD
Polymorphisms : SNP, variants
NCBI Variation ViewerMLH1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MLH1
dbVarMLH1
ClinVarMLH1
1000_GenomesMLH1 
Exome Variant ServerMLH1
ExAC (Exome Aggregation Consortium)MLH1 (select the gene name)
Genetic variants : HAPMAP4292
Genomic Variants (DGV)MLH1 [DGVbeta]
Mutations
ICGC Data PortalMLH1 
TCGA Data PortalMLH1 
Broad Tumor PortalMLH1
OASIS PortalMLH1 [ Somatic mutations - Copy number]
Cancer Gene: CensusMLH1 
Somatic Mutations in Cancer : COSMICMLH1 
intOGen PortalMLH1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Colon cancer gene variant databases
LOVD (Leiden Open Variation Database)LOVD - human mismatch repair genes
LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch MLH1
DgiDB (Drug Gene Interaction Database)MLH1
DoCM (Curated mutations)MLH1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MLH1 (select a term)
intoGenMLH1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)3:37034841-37092337  ENSG00000076242
CONAN: Copy Number AnalysisMLH1 
Mutations and Diseases : HGMDMLH1
OMIM120436    158320    276300    609310   
MedgenMLH1
Genetic Testing Registry MLH1
NextProtP40692 [Medical]
TSGene4292
GENETestsMLH1
Huge Navigator MLH1 [HugePedia]
snp3D : Map Gene to Disease4292
BioCentury BCIQMLH1
ClinGenMLH1 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4292
Chemical/Pharm GKB GenePA240
Drug Sensitivity MLH1
Clinical trialMLH1
Miscellaneous
canSAR (ICR)MLH1 (select the gene name)
Other databaseUMD-MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)). Curator: S. Olschwang
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMLH1
EVEXMLH1
GoPubMedMLH1
iHOPMLH1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Aug 10 18:59:08 CEST 2016

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