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MLH1 Gene

protein-coding   GIFtS: 72
GCID: GC03P037034

MutL Homolog 1

(Previous names: mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type...)
(Previous symbol: COCA2)
  See MLH1-related diseases
at  

(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
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Aliases
MutL Homolog 11 2     HNPCC2
COCA21 2 3 5     DNA Mismatch Repair Protein Mlh12
HNPCC22 5     hMLH12
MutL (E. Coli) Homolog 1 (Colon Cancer, Nonpolyposis Type 2)1     MutL Homolog 1, Colon Cancer, Nonpolyposis Type 22
MutL Homolog 1, Colon Cancer, Nonpolyposis Type 2 (E. Coli)1     MutL Protein Homolog 13
FCC22     

External Ids:    HGNC: 71271   Entrez Gene: 42922   Ensembl: ENSG000000762427   OMIM: 1204365   UniProtKB: P406923   

Export aliases for MLH1 gene to outside databases

Previous GC identifers: GC03P036337 GC03P036848 GC03P036995 GC03P037009 GC03P036976


(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
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Entrez Gene summary for MLH1 Gene:
This gene 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. Alternative splicing results in multiple transcript
variants encoding distinct isoforms. Additional transcript variants have been described, but their full-length
natures have not been determined.(provided by RefSeq, Nov 2009)

GeneCards Summary for MLH1 Gene:
MLH1 (mutL homolog 1) is a protein-coding gene. Diseases associated with MLH1 include mlh1-related lynch syndrome, and solitary rectal ulcer syndrome. GO annotations related to this gene include ATPase activity and MutSalpha complex binding.

UniProtKB/Swiss-Prot: MLH1_HUMAN, P40692
Function: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair
system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA
mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary
complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces
single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade
the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the
newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp
loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to
the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can
lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role
in meiosis

Gene Wiki entry for MLH1 Gene


(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
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RefSeq DNA sequence at NCBI GenBank:
NC_000003.11  NT_022517.19  NC_018914.2  
Regulatory elements:
   Regulatory transcription factor binding sites in the MLH1 gene promoter:
         CREB   SREBP-1a   Pax-6   SREBP-1c   MyoD   MRF-2   AP-2gamma   SREBP-1b   
         Other transcription factors

SwitchGear Promoter luciferase reporter plasmidMLH1 promoter sequence
   Search Chromatin IP Primers for MLH1

Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat MLH1


Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 3p21.3   Ensembl cytogenetic band:  3p22.2   HGNC cytogenetic band: 3p22.3

MLH1 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
MLH1 gene location

GeneLoc information about chromosome 3         GeneLoc Exon Structure

GeneLoc location for GC03P037034:  view genomic region     (about GC identifiers)

Start:
37,034,823 bp from pter      End:
37,107,380 bp from pter
Size:
72,558 bases      Orientation:
plus strand

(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, Cloud-Clone Corp., eBioscience, and/or antibodies-online,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, Cloud-Clone Corp., eBioscience, and/or antibodies-online, Antibodies by EMD Millipore, R&D Systems, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, Cloud-Clone Corp, antibodies-online, and/or others.)
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UniProtKB/Swiss-Prot: MLH1_HUMAN, P40692 (See protein sequence)
Recommended Name: DNA mismatch repair protein Mlh1  
Size: 756 amino acids; 84601 Da
Subunit: Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms
a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome
surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1
protein complex. This association could be a dynamic process changing throughout the cell cycle and within
subnuclear domains. Interacts with MBD4. Interacts with EXO1 and MTMR15/FAN1
2 PDB 3D structures from and Proteopedia for MLH1:
3NA3 (3D)        3RBN (3D)    
Secondary accessions: B4DI13 B4DQ11 E9PCU2
Alternative splicing: 3 isoforms:  P40692-1   P40692-2   P40692-3   (No experimental confirmation available)

Explore the universe of human proteins at neXtProt for MLH1: NX_P40692

Explore proteomics data for MLH1 at MOPED

Post-translational modifications: 

  • Modification sites at neXtProt
  • Modification sites at PhosphoSitePlus

  • See MLH1 Protein Expression from SPIRE MOPED, PaxDB, and MaxQB

    REFSEQ proteins (7 alternative transcripts): 
    NP_000240.1  NP_001161089.1  NP_001161090.1  NP_001161091.1  NP_001245200.1  NP_001245202.1  NP_001245203.1  

    ENSEMBL proteins: 
     ENSP00000231790   ENSP00000407773   ENSP00000416783   ENSP00000387511   ENSP00000392649  
     ENSP00000416687   ENSP00000402667   ENSP00000398272   ENSP00000398392   ENSP00000402564  
     ENSP00000407019   ENSP00000399329   ENSP00000411066   ENSP00000400844   ENSP00000393006  
     ENSP00000416476   ENSP00000444286   ENSP00000443665  
    Reactome Protein details: P40692

    MLH1 Human Recombinant Protein Products:

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    Cloud-Clone Corp. Proteins for MLH1

     
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    antibodies-online proteins for MLH1 (7 products) 

     
    antibodies-online peptides for MLH1

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    antibodies-online kits for MLH1 (8 products) 


    (According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
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    Selected InterPro protein domains (see all 7):
     IPR011186 DNA_mismatch_repair_MLH1
     IPR002099 DNA_mismatch_repair_fam
     IPR020568 Ribosomal_S5_D2-typ_fold
     IPR014762 DNA_mismatch_repair_CS
     IPR003594 HATPase_ATP-bd

    Graphical View of Domain Structure for InterPro Entry P40692

    ProtoNet protein and cluster: P40692

    1 Blocks protein domain: IPB002099 DNA mismatch repair protein

    UniProtKB/Swiss-Prot: MLH1_HUMAN, P40692
    Similarity: Belongs to the DNA mismatch repair MutL/HexB family


    Find genes that share domains with MLH1           About GenesLikeMe


    (According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, genOway,
    transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, Vector BioLabs and/or Addgene, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Flow cytometry from eBioscience, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Molecular Function:

         UniProtKB/Swiss-Prot Summary: MLH1_HUMAN, P40692
    Function: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair
    system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA
    mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary
    complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces
    single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade
    the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the
    newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp
    loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to
    the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can
    lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role
    in meiosis

         Genatlas biochemistry entry for MLH1:
    yeast mutator gene homolog (bacterial mutL),with several spliced isoforms,involved in mismatch repair in non-small
    cell lung cancer (see TSG3B),deleted in sporadic colorectal cancer or mutated with hypermethylation of the
    promoter region,in breast cancer and in sporadic endometrial cancer,interacting with NF1 (predisposition to early
    hematological malignancy) and with PMS2

         Gene Ontology (GO): Selected molecular function terms (see all 8):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0003697contributes to single-stranded DNA binding IDA11809883
    GO:0005515contributes to protein binding IPI16403449
    GO:0005524ATP binding IEA--
    GO:0016887ATPase activity IBA--
    GO:0030983mismatched DNA binding ----
         
    Find genes that share ontologies with MLH1           About GenesLikeMe


    Phenotypes:
         3 GenomeRNAi human phenotypes for MLH1:
     Decreased viability of wild-ty  G0/1 arrest  Increased G1 DNA content 

         8 MGI mutant phenotypes (inferred from 4 alleles(MGI details for Mlh1):
     cellular  digestive/alimentary  endocrine/exocrine gland  homeostasis/metabolism  integument 
     mortality/aging  reproductive system  tumorigenesis 

    Find genes that share phenotypes with MLH1           About GenesLikeMe

    Animal Models:
         MGI mouse knock-outs for MLH1: Mlh1tm1Lisk Mlh1tm1Mse Mlh1tm1Rak

       genOway: Develop your customized and physiologically relevant rodent model for MLH1

    miRNA
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    miRTarBase miRNAs that target MLH1:
    hsa-mir-31-5p (MIRT035519), hsa-mir-30a-5p (MIRT028566), hsa-mir-155-5p (MIRT000461)

    Block miRNA regulation of human, mouse, rat MLH1 using miScript Target Protectors
    Search for qRT-PCR Assays for microRNAs that regulate MLH1
    SwitchGear 3'UTR luciferase reporter plasmidMLH1 3' UTR sequence
    Inhib. RNA
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    Predesigned siRNA for gene silencing in human, mouse, rat MLH1

    Gene Editing
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    Clone
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    (According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Subcellular locations from UniProtKB/Swiss-Prot
    MLH1_HUMAN, P40692: Nucleus
    Subcellular locations from COMPARTMENTS: 

    CompartmentConfidence
    nucleus5
    plasma membrane3
    cytosol1
    mitochondrion1

    Gene Ontology (GO): Selected cellular component terms (see all 11):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000793condensed chromosome ----
    GO:0000794condensed nuclear chromosome ----
    GO:0000795synaptonemal complex IBA--
    GO:0001673male germ cell nucleus IEA--
    GO:0005634nucleus IDA--

    Find genes that share ontologies with MLH1           About GenesLikeMe


    (SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
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    SuperPaths for MLH1 About   (see all 12)  
    See pathways by source

    SuperPathContained pathways About
    1Telomere C-strand (Lagging Strand) Synthesis
    Mismatch repair0.56
    Mismatch repair0.00
    Mismatch Repair in Eukaryotes0.54
    2Meiosis (REACTOME)
    Meiosis0.74
    Meiotic Recombination0.74
    3Endometrial cancer
    Endometrial cancer0.45
    Colorectal cancer0.42
    4Cell Cycle / Checkpoint Control
    Cell Cycle / Checkpoint Control0.32
    DNA Damage0.32
    5Doxorubicin Pathway, Pharmacokinetics
    Doxorubicin Pathway (Cancer Cell), Pharmacodynamics0.43


    Find genes that share SuperPaths with MLH1           About GenesLikeMe

    Pathways by source                                                                                                                                                                 See SuperPaths
    Show all pathways

    2 Downloadable PowerPoint Slides of GeneGlobe Pathway Central Maps for MLH1
        Mismatch Repair in Eukaryotes
    Colorectal Cancer Metastasis

    2 Cell Signaling Technology (CST) Pathways for MLH1
        Cell Cycle / Checkpoint Control
    DNA Damage

    1 GeneGo (Thomson Reuters) Pathway for MLH1
        DNA damage Role of Brca1 and Brca2 in DNA repair

    3 BioSystems Pathways for MLH1
        Mismatch repair
    Ovarian Infertility Genes
    Direct p53 effectors


    1 Reactome Pathway for MLH1
        Meiotic recombination

    2 PharmGKB Pathways for MLH1
        Busulfan Pathway, Pharmacodynamics
    Doxorubicin Pathway (Cancer Cell), Pharmacodynamics

    5 Kegg Pathways  (Kegg details for MLH1):
        Mismatch repair
    Fanconi anemia pathway
    Pathways in cancer
    Colorectal cancer
    Endometrial cancer

        Pathway & Disease-focused RT2 Profiler PCR Arrays including MLH1 (see all 9): 
              Oncogenes & Tumor Suppressor Genes in human mouse rat
              Lung Cancer in human mouse rat
              Leukemia in human mouse rat
              DNA Damage Signaling Pathway in human mouse rat
              Lymphoma in human mouse rat

    Interactions:

        GeneGlobe Interaction Network for MLH1

    STRING Interaction Network Preview (showing 5 interactants - click image to see 25)

    Selected Interacting proteins for MLH1 (P406921, 2, 3 ENSP000002317904) via UniProtKB, MINT, STRING, and/or I2D (see all 803)
    InteractantInteraction Details
    GeneCardExternal ID(s)
    BRIP1Q9BX631, 2, 3, ENSP000002590084EBI-744248,EBI-3509650 MINT-5115529 MINT-5115470 MINT-5115499 MINT-5115319 MINT-5115375 MINT-5115489 MINT-5115552 MINT-5115348 MINT-5115512 MINT-5115404 MINT-5115429 I2D: score=2 STRING: ENSP00000259008
    PMS2P542781, 2, 3, ENSP000002658494EBI-744248,EBI-1162561 MINT-5115348 MINT-5115404 MINT-5115319 MINT-5115375 I2D: score=14 STRING: ENSP00000265849
    SPTAN1Q138131, 2, 3EBI-744248,EBI-351450 MINT-7945693 I2D: score=2 
    BRCA1P383982, 3, ENSP000003502834MINT-5115348 MINT-5115319 MINT-5115375 MINT-5115552 MINT-8141024 I2D: score=3 STRING: ENSP00000350283
    TRIM29Q141342, 3, ENSP000003431294MINT-66539 I2D: score=5 STRING: ENSP00000343129
    About this table

    Gene Ontology (GO): Selected biological process terms (see all 22):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000289nuclear-transcribed mRNA poly(A) tail shortening IEA--
    GO:0000712resolution of meiotic recombination intermediates IEA--
    GO:0002204somatic recombination of immunoglobulin genes involved in immune response ----
    GO:0006200ATP catabolic process IBA--
    GO:0006281DNA repair ----

    Find genes that share ontologies with MLH1           About GenesLikeMe



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
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    Browse Small Molecules at EMD Millipore
       Browse drugs & compounds from Enzo Life Sciences
      Browse compounds at ApexBio 

    Browse Tocris compounds for MLH1

    Selected Novoseek inferred chemical compound relationships for MLH1 gene (see all 65)    About this table
    Compound   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    mononucleotide 85.1 19 17504984 (2), 10675487 (1), 12479849 (1), 10674020 (1) (see all 17)
    crcs 84.7 35 15294875 (3), 18257912 (3), 15749592 (2), 18618713 (2) (see all 20)
    mhs-2 73.8 2 9616736 (1), 7576988 (1)
    o6-methylguanine 63.7 15 17276933 (2), 16436636 (1), 19047896 (1), 14633667 (1) (see all 14)
    5-aza-2'deoxycytidine 56.2 40 19306077 (4), 11085525 (4), 19742343 (4), 12794758 (3) (see all 12)
    6 thioguanine 50.2 19 9485033 (4), 9973196 (2), 19603033 (2), 9233776 (1) (see all 8)
    temozolomide 44.3 7 11138465 (2), 14985452 (2), 19741564 (1), 14585987 (1)
    sodium bisulfite 43.3 2 11798868 (1), 15342451 (1)
    mnng 41.9 15 9750018 (4), 7641183 (3), 8044777 (1), 16085492 (1)
    paraffin 35.7 13 15881919 (1), 11376026 (1), 11788563 (1), 12400605 (1) (see all 12)



    Find genes that share compounds with MLH1           About GenesLikeMe



    (Secondary structures according to fRNAdb,
    GenBank/EMBL/DDBJ Accessions according to
    Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
    RefSeq according to Entrez Gene,
    DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
    exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
    siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
    Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, and/or Addgene, Primers from OriGene, and/or QIAGEN, Flow cytometry from eBioscience )
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    REFSEQ mRNAs for MLH1 gene (7 alternative transcripts): 
    NM_000249.3  NM_001167617.1  NM_001167618.1  NM_001167619.1  NM_001258271.1  NM_001258273.1  NM_001258274.1  

    Unigene Cluster for MLH1:

    MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
    Hs.195364  [show with all ESTs]
    Unigene Representative Sequence: NM_000249
    Selected Ensembl transcripts including schematic representations, and UCSC links where relevant (see all 22):
    ENST00000231790(uc003cgl.3 uc011ayb.2 uc010hge.3) ENST00000457004
    ENST00000432299 ENST00000442249 ENST00000454028 ENST00000456676(uc010hgg.1 uc010hgh.1 uc010hgi.1 uc010hgj.1 uc010hgl.1)
    ENST00000458205(uc011ayc.2 uc011ayd.2 uc003cgo.3 uc003cgn.4 uc010hgk.3 uc010hgn.3 uc010hgm.3 uc010hgo.3 uc010hgp.3 uc010hgq.3)
    ENST00000476172 ENST00000455445 ENST00000441265 ENST00000435176 ENST00000429117
    ENST00000492474 ENST00000466900 ENST00000485889 ENST00000447829 ENST00000458009
    ENST00000413212
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    Additional mRNA sequence: 

    AB209848.1 AK222810.1 AK295359.1 AK298324.1 AK298583.1 AK302807.1 AK311326.1 AK311365.1 
    AK312609.1 AK316074.1 AK316264.1 AY517558.1 BC006850.1 BX648844.1 DQ648888.1 DQ648889.1 
    DQ648890.1 DQ648891.1 DQ648892.1 DQ648893.1 EU188665.1 EU188666.1 EU188667.1 EU188668.1 
    EU188669.1 EU188670.1 EU188671.1 EU188672.1 EU188673.1 EU188674.1 EU188675.1 EU188676.1 
    U07343.1 U07418.1 

    20 DOTS entries:

    DT.445647  DT.100810259  DT.100810263  DT.95333713  DT.100810264  DT.101980402  DT.100028705  DT.100761169 
    DT.120922994  DT.92442427  DT.99999999  DT.120923036  DT.92442423  DT.97846810  DT.100760267  DT.100810256 
    DT.95156564  DT.100742075  DT.91798978  DT.99993535 

    Selected AceView cDNA sequences (see all 278):

    BX386294 AL531062 BU735633 U07343 AA343536 BM998444 BM719189 AU124504 
    AI276652 CD644706 BE552260 CB529333 AA343535 CA944649 CB142573 BU621288 
    BU176348 CA391710 CB155128 CR609870 CD657532 AA347097 BM452736 BP373445 

    GeneLoc Exon Structure

    Selected Alternative Splicing Database (ASD) splice patterns (SP) for MLH1 (see all 9)    About this scheme

    ExUns: 1a · 1b ^ 2 ^ 3 ^ 4 ^ 5 ^ 6a · 6b ^ 7 ^ 8 ^ 9 ^ 10 ^ 11a · 11b ^ 12 ^ 13a · 13b ^ 14 ^ 15a · 15b · 15c ^ 16 ^ 17 ^ 18 ^ 19a · 19b ^
    SP1:                                                                                            -           -                                         -         
    SP2:              -           -                                                                 -           -                                         -         
    SP3:              -           -                                                                 -           -                                         -         
    SP4:                                                                                            -                                                               
    SP5:                                                                                      -     -     -     -                                                   

    ExUns: 20 ^ 21a · 21b ^ 22a · 22b
    SP1:                              
    SP2:                              
    SP3:  -     -     -               
    SP4:                              
    SP5:                              


    ECgene alternative splicing isoforms for MLH1

    (RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
    About This Section

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    MLH1 expression in normal human tissues (normalized intensities)
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS <intensity>2/3
    CGAP TAG: CTTGCCTTAG
    MLH1 Expression
    About this image


    MLH1 expression in embryonic tissues and stem cells    About this table
    Data from LifeMap, the Embryonic Development and Stem Cells Database
     selected tissues (see all 6) fully expand
     
     Brain (Nervous System)    fully expand to see all 3 entries
             Cerebral Cortex
     
     Testis (Reproductive System)    fully expand to see all 2 entries
             Primary Spermatocyte Seminiferous Tubules
     
     Trophoblast (Extraembryonic Tissues)
             Trophoblast Cells Trophoblast
     
     Ovary (Reproductive System)
             Oviduct
     
     Bone (Muscoskeletal System)
             Bone Marrow
    MLH1 Protein expression data from MOPED1, PaxDb2 and MaxQB3    About this image

    MLH1 Protein Expression

    SOURCE GeneReport for Unigene cluster: Hs.195364

    UniProtKB/Swiss-Prot: MLH1_HUMAN, P40692
    Tissue specificity: Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart

        Pathway & Disease-focused RT2 Profiler PCR Arrays including MLH1 (see all 9): 
              Oncogenes & Tumor Suppressor Genes in human mouse rat
              Lung Cancer in human mouse rat
              Leukemia in human mouse rat
              DNA Damage Signaling Pathway in human mouse rat
              Lymphoma in human mouse rat

    Primer
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    QuantiFast Probe-based Assays in human, mouse, rat MLH1
    In Situ
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    Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for MLH1

    (Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
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    This gene was present in the common ancestor of eukaryotes.

    Orthologs for MLH1 gene from Selected species (see all 23)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    mouse
    (Mus musculus)
    Mammalia Mlh11 , 5 mutL homolog 1 (E. coli)1, 5 87.13(n)1
    88.89(a)1
      9 (60.92 cM)5
    173501  NM_026810.21  NP_081086.21 
     1112282285 
    chicken
    (Gallus gallus)
    Aves MLH11 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. more 73.47(n)
    80.11(a)
      420729  XM_418828.2  XP_418828.1 
    lizard
    (Anolis carolinensis)
    Reptilia MLH16
    mutL homolog 1
    78(a)
    1 ↔ 1
    6(43631662-43672812)
    African clawed frog
    (Xenopus laevis)
    Amphibia CD302763.12   -- 75.12(n)    CD302763.1 
    zebrafish
    (Danio rerio)
    Actinopterygii zgc663012 hypothetical protein MGC66301 75.55(n)   393632  BC057507.1 
    fruit fly
    (Drosophila melanogaster)
    Insecta Mlh11 , 3 mismatch repair3
    Mlh11
    58(a)3
    56.06(n)1
    52.66(a)1
      44B93
    357961  NM_057674.31  NP_477022.11 
    worm
    (Caenorhabditis elegans)
    Secernentea mlh-13 DNA mismatch repair protein 32(a)   III(13580631-13586072)   --
    baker's yeast
    (Saccharomyces cerevisiae)
    Saccharomycetes MLH1(YMR167W)4
    MLH11
    Protein required for mismatch repair in mitosis and more4
    MLH11
    47.89(n)1
    40.5(a)1
      13(594886-597195)4
    8552031, 4  NP_013890.11, 4 
    thale cress
    (Arabidopsis thaliana)
    eudicotyledons MLH11 MLH1 52.3(n)
    46.11(a)
      826493  NM_116983.2  NP_567345.2 
    rice
    (Oryza sativa)
    Liliopsida Os.109002 Oryza sativa (japonica cultivar-group) cDNA cloneJ more 77.75(n)    AK070111.1 


    ENSEMBL Gene Tree for MLH1 (if available)
    TreeFam Gene Tree for MLH1 (if available)

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
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    Paralogs for MLH1 gene
    4 SIMAP similar genes for MLH1 using alignment to 37 protein entries:     MLH1_HUMAN (see all proteins):
    DKFZp686J1569    PMS8    PMS1    PMS5

    Find genes that share paralogs with MLH1           About GenesLikeMe



    (SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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    Selected SNPs for MLH1 (see all 2030)    About this table                                 

    Genomic DataTranscription Related DataAllele Frequencies
    SNP IDValidClinical
    significance
    Chr 3 posSequence#AA
    Chg
    TypeMore#Allele
    freq
    PopTotal
    sample
    More
    ----------
    rs637510491,2,,4
    C,FHereditary non-polyposis colorectal cancer 2 (HNPCC2)4 unknown136993916(+) GCGGGT/CGCAGC 14 /A /V mis11Minor allele frequency- C:0.00NA 4548
    rs637517131,2,,4
    CHereditary non-polyposis colorectal cancer 2 (HNPCC2)4 untested137021039(+) CACCGC/G/TTCTTT 21 L V F mis10--------
    rs637504491,2,,4
    C,FColorectal cancer4 untested137021148(+) GAAGAA/C/GGGCTG 21 K T R mis12NA EU 5873
    VAR_0044414
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0044412 R K mis40--------
    VAR_0044394
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0044392 G R mis40--------
    VAR_0129164
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0129162 S T mis40--------
    VAR_0433924
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0433922 D E mis40--------
    VAR_0433904
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0433902 D G mis40--------
    VAR_0434034
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0434032 A G mis40--------
    VAR_0044334
    Hereditary non-polyposis colorectal cancer 2 (HNPCC2)4--see VAR_0044332 P L mis40--------

    HapMap Linkage Disequilibrium report for MLH1 (37034823 - 37107380 bp)

    Structural Variations
         Database of Genomic Variants (DGV) 3 variations for MLH1:    About this table    
    Variant IDTypeSubtypePubMed ID
    esv1133148CNV Deletion17803354
    nsv834662CNV Loss17160897
    nsv834663CNV Loss17160897

    Human Gene Mutation Database (HGMD): MLH1
    Locus Specific Mutation Databases (LSDB): MLH1

    Selected Site Specific Mutation Identification with PCR Assays for MLH1 (see all 6):
    Cosmic IdAA Change
    26798p.S252*
    25900p.S556fs*14
    26802p.S505fs*3
    26084p.C233R
    29727p.R100*
    SeqTarget long-range PCR primers for resequencing MLH1
    DNA2.0 Custom Variant and Variant Library Synthesis for MLH1

    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Novoseek, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
    About This Section

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    OMIM gene information: 120436   
    OMIM disorders: 609310  276300  158320  
    UniProtKB/Swiss-Prot: MLH1_HUMAN, P40692
  • Hereditary non-polyposis colorectal cancer 2 (HNPCC2) [MIM:609310]: An autosomal dominant disease
    associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to
    early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female
    reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western
    world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary
    predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II
    is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach,
    small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the
    Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other
    two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of
    hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families
    who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is
    strongly suspected. Note=The disease is caused by mutations affecting the gene represented in this entry
  • Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: Autosomal dominant disorder characterized by
    malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous
    cysts, hyperpigmented and cafe au lait spots. Note=The disease is caused by mutations affecting the gene
    represented in this entry
  • Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous
    neoplasms and visceral malignancy. Note=The disease is caused by mutations affecting the gene represented in this
    entry
  • Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic
    disease of the breast
  • Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus.
    Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other
    fluids. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry
  • Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic
    inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in
    whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These
    individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced,
    which demonstrates that an epimutation can phenocopy a genetic disease

  • Selected diseases for MLH1 (see all 26):    
    About MalaCards
    mlh1-related lynch syndrome    solitary rectal ulcer syndrome    esophageal disease    colorectal cancer, hereditary nonpolyposis, type 2
    mlh1-related muir-torre syndrome    chromosome 3p deletion    anal fistula    mlh1-related turcot syndrome
    female breast carcinoma    colorectal cancer 2    muir-torre syndrome    lynch syndrome
    meier-gorlin syndrome 2    atypical polypoid adenomyoma    monophasic synovial sarcoma    turcot syndrome
    gallbladder cancer    in situ carcinoma    colon cancer    li-fraumeni syndrome

    9 diseases from the University of Copenhagen DISEASES database for MLH1:
    Lynch syndrome     Colorectal cancer     Endometrial cancer     Carcinoma
    Adenoma     Familial adenomatous polyposis     Ovarian cancer     Sebaceous carcinoma
    Small intestine carcinoma

    Find genes that share disorders with MLH1           About GenesLikeMe

    Selected Novoseek inferred disease relationships for MLH1 gene (see all 95)    About this table

    Disease   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    microsatellite instability 98.1 530 16941012 (6), 11601928 (5), 11870540 (4), 16569647 (4) (see all 99)
    lynch syndrome 95.2 130 19949877 (9), 16143124 (4), 19526325 (4), 17973250 (3) (see all 72)
    colorectal cancer 94.1 1282 15294875 (8), 10922385 (8), 18547406 (7), 9399661 (6) (see all 99)
    hereditary nonpolyposis colon cancer 90.1 27 8895729 (2), 16736289 (2), 9927034 (2), 11179758 (2) (see all 23)
    germ-line mutation 85.5 75 11093816 (3), 18331697 (3), 9419403 (3), 9709044 (2) (see all 50)
    muir-torre syndrome 84.9 9 7616541 (1), 10815898 (1), 16826164 (1), 11859205 (1) (see all 9)
    colorectal carcinoma 83.3 98 10418831 (3), 12673483 (3), 15239345 (3), 9087566 (3) (see all 68)
    endometrial cancer 83 93 10938395 (4), 12700670 (3), 10072435 (3), 14760069 (3) (see all 58)
    colon cancer 79.9 121 11221878 (4), 11857087 (3), 15017620 (3), 20444249 (3) (see all 78)
    cancer 78.5 415 16106253 (6), 19855373 (4), 12861399 (4), 10861263 (4) (see all 99)

    GeneTests: MLH1
    GeneReviews: MLH1
    Genetic Association Database (GAD): MLH1
    Human Genome Epidemiology (HuGE) Navigator: MLH1 (227 documents)

    Export disorders for MLH1 gene to outside databases

    (in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
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    PubMed articles for MLH1 gene, integrated from 10 sources (see all 1867):
    (articles sorted by number of sources associating them with MLH1)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. 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. (PubMed id 14961575)1, 2, 4, 9 Cederquist K.... Groenberg H. (Int. J. Cancer 2004)
    2. Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. (PubMed id 14635101)1, 2, 4, 9 Taylor C.F.... Taylor G.R. (Hum. Mutat. 2003)
    3. Missense mutations in hMLH1 associated with colorectal cancer. (PubMed id 10598809)1, 2, 4, 9 Liu T.... Lindblom A. (Hum. Genet. 1999)
    4. Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. (PubMed id 18033691)1, 2, 4, 9 Barnetson R.A....Dunlop M.G. (Hum. Mutat. 2008)
    5. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. (PubMed id 8145827)1, 2, 4, 9 Bronner C.E.... Liskay R.M. (Nature 1994)
    6. 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? (PubMed id 11726306)1, 2, 4 Mueller-Koch Y.... Holinski-Feder E. (Eur. J. Med. Res. 2001)
    7. The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population. (PubMed id 18547406)1, 4, 9 Christensen L.L....Orntoft T.F. (BMC Med. Genet. 2008)
    8. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). (PubMed id 17939062)1, 4, 9 Geary J....Hodgson S.V. (Fam. Cancer 2008)
    9. The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. (PubMed id 16106253)1, 4, 9 Lawes D.A....Boulos P.B. (Br. J. Cancer 2005)
    10. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. (PubMed id 20028567)1, 4, 9 Ramsoekh D....Kuipers E.J. (Hered Cancer Clin Pract 2009)

    (in PubMed, OMIM, and NCBI Bookshelf)
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     ANDOR
    Aliases
    Disorders
    Free Text  

      Query String
    PubMed
    OMIM
    NCBI Bookshelf
      (Note: In FireFox, select the above section and copy using Ctrl-C)

    (According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
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    Entrez Gene: 4292 HGNC: 7127 AceView: MLH1 Ensembl:ENSG00000076242 euGenes: HUgn4292
    ECgene: MLH1 Kegg: 4292 H-InvDB: MLH1

    (According to HUGE)
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      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
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    NameDescription
    PharmGKB entry for MLH1 Pharmacogenomics, SNPs, Pathways
    ATLAS Chromosomes in Cancer entry for MLH1 Genetics and Cytogenetics in Oncology and Haematology
    Hereditary non-polyposis colorectal cancer dbhttp://www.nfdht.nl/
    GeneReviewshttp://www.ncbi.nlm.nih.gov/books/NBK1116/?term=MLH1[genesymbol]
    NIEHS-SNPshttp://egp.gs.washington.edu/data/mlh1/

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
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    Patent Information for MLH1 gene:
    Search GeneIP for patents involving MLH1

    GeneCards and IP:
    Japan Patent Office Licenses GeneCards     European Patent Office Licenses GeneCards     Improving the IP Search



    (Antibodies, recombinant proteins, and assays from EMD Millipore, R&D Systems, OriGene, QIAGEN, GenScript, Cell Signaling Technology, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Cloud-Clone Corp., Thermo Fisher Scientific, eBioscience, antibodies-online, and/or others, Gene Editing from DNA2.0. Clones from OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Addgene, Cell lines from GenScript, and ESI BIO, Flow cytometery from eBioscience, PCR Arrays from QIAGEN, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, Enzo Life Sciences, and/or ApexBio, In Situ Hybridization Assays from
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    GeneCards Homepage - Last full update: 7 May 2014 - Incrementals: 9 May 2014 , 2 Jun 2014 , 26 Jun 2014 , 30 Jun 2014 , 21 Aug 2014 , 8 Sep 2014 , 7 Oct 2014

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