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    MLH3 mutL homolog 3 [ Homo sapiens (human) ]

    Gene ID: 27030, updated on 3-Apr-2024

    Summary

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    Official Symbol
    MLH3provided by HGNC
    Official Full Name
    mutL homolog 3provided by HGNC
    Primary source
    HGNC:HGNC:7128
    See related
    Ensembl:ENSG00000119684 MIM:604395; AllianceGenome:HGNC:7128
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    HNPCC7
    Summary
    This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
    Expression
    Ubiquitous expression in thyroid (RPKM 5.0), adrenal (RPKM 3.9) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    14q24.3
    Exon count:
    14
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 14 NC_000014.9 (75013775..75051467, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 14 NC_060938.1 (69222838..69260934, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 14 NC_000014.8 (75480478..75518170, complement)

    Chromosome 14 - NC_000014.9Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC107984690 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5936 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5937 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5938 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8733 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr14:75431938-75433137 Neighboring gene placental growth factor Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:75446625-75447250 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:75447251-75447876 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:75447877-75448500 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8734 Neighboring gene H3K27ac hESC enhancer GRCh37_chr14:75469302-75469982 Neighboring gene eukaryotic translation initiation factor 2B subunit beta Neighboring gene RNA, U6 small nuclear 689, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5939 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8735 Neighboring gene H3K27ac hESC enhancer GRCh37_chr14:75535987-75536538 Neighboring gene H3K27ac hESC enhancer GRCh37_chr14:75536539-75537090 Neighboring gene acylphosphatase 1 Neighboring gene zinc finger C2HC-type containing 1C Neighboring gene NIMA related kinase 9

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Exonic sequencing and MLH3 gene expression analysis of breast cancer patients. Khailany RA, et al. Cell Mol Biol (Noisy-le-grand), 2021 Nov 25. PMID 34933735
    2. A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia. Nawaz S, et al. J Hum Genet, 2021 Jul. PMID 33517345
    3. Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition. Olkinuora A, et al. Genet Med, 2019 Aug. PMID 30573798, Free PMC Article
    4. GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one. Halabi A, et al. Nucleic Acids Res, 2018 May 4. PMID 29529236, Free PMC Article
    5. Coexistence of MLH3 germline variants in colon cancer patients belonging to families with Lynch syndrome-associated brain tumors. Duraturo F, et al. J Neurooncol, 2016 Sep. PMID 27401157

    See all (67) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Exonic sequencing and MLH3 gene expression analysis of breast cancer patients.
      Title: Exonic sequencing and MLH3 gene expression analysis of breast cancer patients.
    2. A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia.
      Title: A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia.
    3. Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination.
      Title: Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination.
    4. Regulation of the MLH1-MLH3 endonuclease in meiosis.
      Title: Regulation of the MLH1-MLH3 endonuclease in meiosis.
    5. MutLgamma, the MLH1-MLH3 heterodimer, is a unique endonuclease that can initiate triplet repeat DNA expansions.
      Title: Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.
    6. rs175080 in MLH3 was not significantly different between idiopathic male infertility and control (p > 0.05).
      Title: The association of four SNPs in DNA mismatch repair genes with idiopathic male infertility in northwest China.
    7. Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
      Title: Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.
    8. MLH3 isoform 1 is active in GAA*TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not.
      Title: GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one.
    9. The effects of chronic smoking on oral mucosa led to the methylation of genes MRE11A PMS2, XRCC1 and MLH3, but resulted in a reduction of gene expression of MRE11A and PMS2, which showed >/=50% methylation. These results provide evidence that smoking cause methylation and reduced expression of repair genes.
      Title: Screening methylation of DNA repair genes in the oral mucosa of chronic smokers.
    10. MLH3 germline variants are associated with colon cancer patients belonging to families with Lynch syndrome-associated brain tumors.
      Title: Coexistence of MLH3 germline variants in colon cancer patients belonging to families with Lynch syndrome-associated brain tumors.
    Submit: New GeneRIF Correction See all GeneRIFs (34)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Colorectal cancer
    MedGen: C0346629 OMIM: 114500 GeneReviews: Lynch Syndrome
    		Compare labs
    Colorectal cancer, hereditary nonpolyposis, type 7
    MedGen: C1858380 OMIM: 614385 GeneReviews: Not available
    		Compare labs
    Endometrial carcinoma
    MedGen: C0476089 OMIM: 608089 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • MGC138372

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables ATP hydrolysis activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables ATP-dependent DNA damage sensor activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables centromeric DNA binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables chromatin binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables mismatched DNA binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables satellite DNA binding TAS
    Traceable Author Statement
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in female meiosis I IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in male meiotic nuclear division IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in mismatch repair IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in mismatch repair NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in protein localization IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in reciprocal meiotic recombination NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in synaptonemal complex assembly IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in chiasma IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in male germ cell nucleus IEA
    Inferred from Electronic Annotation
    more info
    		  
    part_of mismatch repair complex IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in nucleus TAS
    Traceable Author Statement
    more info
    		 PubMed 
    located_in synaptonemal complex IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    DNA mismatch repair protein Mlh3

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_008649.1 RefSeqGene

      Range
      5001..42769
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_217

    mRNA and Protein(s)

    1. NM_001040108.2 → NP_001035197.1  DNA mismatch repair protein Mlh3 isoform 1

      See identical proteins and their annotated locations for NP_001035197.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AB039667, AL049780, BX090851, DA805814
      Consensus CDS
      CCDS32123.1
      UniProtKB/Swiss-Prot
      P49751, Q56DK9, Q9P292, Q9UHC0, Q9UHC1
      UniProtKB/TrEMBL
      Q2M1Z1
      Related
      ENSP00000348020.2, ENST00000355774.7
      Conserved Domains (3) summary
      smart00853
      Location:1191 → 1370
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    2. NM_014381.3 → NP_055196.2  DNA mismatch repair protein Mlh3 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2), also known as delta7, lacks an alternate in-frame exon, compared to variant 1, resulting in a shorter protein (isoform 2), compared to isoform 1.
      Source sequence(s)
      AL049780, BC112167, BX090851, DA731365, DA805814
      Consensus CDS
      CCDS9837.1
      UniProtKB/TrEMBL
      Q2M1Z1
      Related
      ENSP00000370355.3, ENST00000380968.6
      Conserved Domains (3) summary
      smart00853
      Location:1191 → 1346
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000014.9 Reference GRCh38.p14 Primary Assembly

      Range
      75013775..75051467 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047431265.1 → XP_047287221.1  DNA mismatch repair protein Mlh3 isoform X4

    2. XM_024449538.2 → XP_024305306.1  DNA mismatch repair protein Mlh3 isoform X3

      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1156 → 1335
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      cl28386
      Location:1 → 269
      MutL; DNA mismatch repair ATPase MutL [Replication, recombination and repair]

    3. XM_017021219.3 → XP_016876708.1  DNA mismatch repair protein Mlh3 isoform X2

      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1191 → 1346
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    4. XM_006720116.5 → XP_006720179.1  DNA mismatch repair protein Mlh3 isoform X1

      See identical proteins and their annotated locations for XP_006720179.1

      UniProtKB/Swiss-Prot
      P49751, Q56DK9, Q9P292, Q9UHC0, Q9UHC1
      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1191 → 1370
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    5. XM_005267533.6 → XP_005267590.1  DNA mismatch repair protein Mlh3 isoform X4

      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1156 → 1311
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    6. XM_005267532.6 → XP_005267589.1  DNA mismatch repair protein Mlh3 isoform X3

      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1156 → 1335
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      cl28386
      Location:1 → 269
      MutL; DNA mismatch repair ATPase MutL [Replication, recombination and repair]

    7. XM_047431266.1 → XP_047287222.1  DNA mismatch repair protein Mlh3 isoform X5

    8. XM_047431268.1 → XP_047287224.1  DNA mismatch repair protein Mlh3 isoform X8

    9. XM_005267534.4 → XP_005267591.1  DNA mismatch repair protein Mlh3 isoform X7

      UniProtKB/TrEMBL
      Q2M1Z1
      Conserved Domains (3) summary
      smart00853
      Location:1191 → 1275
      MutL_C; MutL C terminal dimerisation domain
      cd03486
      Location:206 → 349
      MutL_Trans_MLH3; MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to ...
      pfam02518
      Location:22 → 115
      HATPase_c; Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

    10. XM_047431267.1 → XP_047287223.1  DNA mismatch repair protein Mlh3 isoform X6

    11. XM_047431269.1 → XP_047287225.1  DNA mismatch repair protein Mlh3 isoform X9

    RNA

    1. XR_007064005.1 RNA Sequence

    2. XR_007064004.1 RNA Sequence

    3. XR_001750225.3 RNA Sequence

    4. XR_245681.5 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060938.1 Alternate T2T-CHM13v2.0

      Range
      69222838..69260934 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054375855.1 → XP_054231830.1  DNA mismatch repair protein Mlh3 isoform X2

    2. XM_054375857.1 → XP_054231832.1  DNA mismatch repair protein Mlh3 isoform X3

    3. XM_054375859.1 → XP_054231834.1  DNA mismatch repair protein Mlh3 isoform X4

    4. XM_054375854.1 → XP_054231829.1  DNA mismatch repair protein Mlh3 isoform X1

    5. XM_054375858.1 → XP_054231833.1  DNA mismatch repair protein Mlh3 isoform X4

    6. XM_054375856.1 → XP_054231831.1  DNA mismatch repair protein Mlh3 isoform X3

    7. XM_054375860.1 → XP_054231835.1  DNA mismatch repair protein Mlh3 isoform X5

    8. XM_054375863.1 → XP_054231838.1  DNA mismatch repair protein Mlh3 isoform X8

    9. XM_054375862.1 → XP_054231837.1  DNA mismatch repair protein Mlh3 isoform X7

    10. XM_054375861.1 → XP_054231836.1  DNA mismatch repair protein Mlh3 isoform X6

    11. XM_054375864.1 → XP_054231839.1  DNA mismatch repair protein Mlh3 isoform X9

    RNA

    1. XR_008488857.1 RNA Sequence

    2. XR_008488856.1 RNA Sequence

    3. XR_008488855.1 RNA Sequence

    4. XR_008488854.1 RNA Sequence

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9UHC1.3 GenPept UniProtKB/Swiss-Prot:Q9UHC1

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