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MLH1 (human mutL homolog 1)

Identity

Other namesCOCA2
FCC2
hMLH1
HNPCC2
HGNC (Hugo) MLH1
LocusID (NCBI) 4292
Location 3p22.2
Location_base_pair Starts at 37034841 and ends at 37092337 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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).
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

External links

Nomenclature
HGNC (Hugo)MLH1   7127
Cards
AtlasMLH1ID149ch3p21
Entrez_Gene (NCBI)MLH1  4292  mutL homolog 1
GeneCards (Weizmann)MLH1
Ensembl (Hinxton)ENSG00000076242 [Gene_View]  chr3:37034841-37092337 [Contig_View]  MLH1 [Vega]
ICGC DataPortalENSG00000076242
cBioPortalMLH1
AceView (NCBI)MLH1
Genatlas (Paris)MLH1
WikiGenes4292
SOURCE (Princeton)NM_000249 NM_001167617 NM_001167618 NM_001167619 NM_001258271 NM_001258273 NM_001258274
Genomic and cartography
GoldenPath (UCSC)MLH1  -  3p22.2   chr3:37034841-37092337 +  3p22.3   [Description]    (hg19-Feb_2009)
EnsemblMLH1 - 3p22.3 [CytoView]
Mapping of homologs : NCBIMLH1 [Mapview]
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)AC_000135 NC_000003 NC_018914 NG_007109 NT_022517 NW_001838877 NW_004929309
Consensus coding sequences : CCDS (NCBI)MLH1
Cluster EST : UnigeneHs.195364 [ NCBI ]
CGAP (NCI)Hs.195364
Alternative Splicing : Fast-db (Paris)GSHG0020691
Alternative Splicing GalleryENSG00000076242
Gene ExpressionMLH1 [ NCBI-GEO ]     MLH1 [ SEEK ]   MLH1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP40692 (Uniprot)
NextProtP40692  [Medical]
With graphics : InterProP40692
Splice isoforms : SwissVarP40692 (Swissvar)
Domaine pattern : Prosite (Expaxy)DNA_MISMATCH_REPAIR_1 (PS00058)   
Domains : Interpro (EBI)DNA_mismatch_repair_C [organisation]   DNA_mismatch_repair_CS [organisation]   DNA_mismatch_repair_fam [organisation]   DNA_mismatch_repair_MLH1/HexB [organisation]   HATPase_ATP-bd [organisation]   Ribosomal_S5_D2-typ_fold [organisation]   Ribosomal_S5_D2-typ_fold_subgr [organisation]  
Related proteins : CluSTrP40692
Domain families : Pfam (Sanger)DNA_mis_repair (PF01119)   
Domain families : Pfam (NCBI)pfam01119   
Domain families : Smart (EMBL)HATPase_c (SM00387)  
DMDM Disease mutations4292
Blocks (Seattle)P40692
PDB (SRS)3NA3    3RBN    4P7A   
PDB (PDBSum)3NA3    3RBN    4P7A   
PDB (IMB)3NA3    3RBN    4P7A   
PDB (RSDB)3NA3    3RBN    4P7A   
Human Protein AtlasENSG00000076242 [gene] [tissue] [antibody] [cell] [cancer]
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
InParanoidP40692
Interologous Interaction database P40692
IntegromeDBMLH1
STRING (EMBL)MLH1
Ontologies - Pathways
Ontology : AmiGOnuclear-transcribed mRNA poly(A) tail shortening  resolution of meiotic recombination intermediates  synaptonemal complex  male germ cell nucleus  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleus  nucleus  chiasma  nucleolus  ATP catabolic process  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  somatic hypermutation of immunoglobulin genes  ATPase activity  guanine/thymine mispair binding  MutLalpha complex  MutSalpha complex binding  meiotic metaphase I plate congression  isotype switching  negative regulation of mitotic recombination  oogenesis  spindle midzone assembly involved in meiosis  
Ontology : EGO-EBInuclear-transcribed mRNA poly(A) tail shortening  resolution of meiotic recombination intermediates  synaptonemal complex  male germ cell nucleus  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleus  nucleus  chiasma  nucleolus  ATP catabolic process  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  somatic hypermutation of immunoglobulin genes  ATPase activity  guanine/thymine mispair binding  MutLalpha complex  MutSalpha complex binding  meiotic metaphase I plate congression  isotype switching  negative regulation of mitotic recombination  oogenesis  spindle midzone assembly involved in meiosis  
Pathways : KEGGMismatch repair    Fanconi anemia pathway    Pathways in cancer    Colorectal cancer    Endometrial cancer   
Protein Interaction DatabaseMLH1
Wikipedia pathwaysMLH1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MLH1
snp3D : Map Gene to Disease4292
SNP (GeneSNP Utah)MLH1
SNP : HGBaseMLH1
Genetic variants : HAPMAPMLH1
Exome VariantMLH1
1000_GenomesMLH1 
ICGC programENSG00000076242 
Cancer Gene: CensusMLH1 
Somatic Mutations in Cancer : COSMICMLH1 
CONAN: Copy Number AnalysisMLH1 
Mutations and Diseases : HGMDMLH1
Mutations and Diseases : intOGenMLH1
Genomic VariantsMLH1  MLH1 [DGVbeta]
dbVarMLH1
ClinVarMLH1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM120436    158320    276300    609310   
MedgenMLH1
GENETestsMLH1
Disease Genetic AssociationMLH1
Huge Navigator MLH1 [HugePedia]  MLH1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMLH1
Homology/Alignments : Family Browser (UCSC)MLH1
Phylogenetic Trees/Animal Genes : TreeFamMLH1
Chemical/Protein Interactions : CTD4292
Chemical/Pharm GKB GenePA240
Drug Sensitivity MLH1
Clinical trialMLH1
Cancer Resource (Charite)ENSG00000076242
Other databases
Other databaseUMD-MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)). Curator: S. Olschwang
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineMLH1
iHOPMLH1
OncoSearchMLH1

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 articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written02-2005Enrico 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. 2005;9(2):120-122.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/MLH1ID149ch3p21.html

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indexed on : Tue Sep 23 19:24:55 CEST 2014

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