Human Gene MLH3 (uc001xrd.1) Description and Page Index
  Description: Homo sapiens mutL homolog 3 (E. coli) (MLH3), transcript variant 1, mRNA.
RefSeq Summary (NM_001040108): 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].
Transcript (Including UTRs)
   Position: hg19 chr14:75,480,467-75,518,235 Size: 37,769 Total Exon Count: 13 Strand: -
Coding Region
   Position: hg19 chr14:75,483,785-75,516,358 Size: 32,574 Coding Exon Count: 12 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-14

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr14:75,480,467-75,518,235)mRNA (may differ from genome)Protein (1453 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
GeneNetworkH-INVHGNCLynxMGIneXtProt
OMIMPubMedReactomeStanford SOURCETreefamUniProtKB
Wikipedia

-  Comments and Description Text from UniProtKB
  ID: MLH3_HUMAN
DESCRIPTION: RecName: Full=DNA mismatch repair protein Mlh3; AltName: Full=MutL protein homolog 3;
FUNCTION: Probably involved in the repair of mismatches in DNA.
SUBUNIT: Heterodimer of MLH1 and MLH3. Interacts with MTMR15/FAN1.
SUBCELLULAR LOCATION: Nucleus (Potential).
TISSUE SPECIFICITY: Ubiquitous.
DISEASE: Defects in MLH3 are the cause of hereditary non-polyposis colorectal cancer type 7 (HNPCC7) [MIM:614385]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers 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, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an 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.
DISEASE: Defects in MLH3 are a cause of colorectal cancer (CRC) [MIM:114500].
SIMILARITY: Belongs to the DNA mismatch repair MutL/HexB family.
SEQUENCE CAUTION: Sequence=AAC42005.1; Type=Frameshift; Positions=Several; Sequence=AAC42005.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part;
WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/mlh3/";

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): MLH3
CDC HuGE Published Literature: MLH3
Positive Disease Associations: head and neck cancer lung cancer , mammalian microsatellite instability
Related Studies:
  1. head and neck cancer lung cancer
    Michiels, S. et al. 2007, Polymorphism discovery in 62 DNA repair genes and haplotype-associations with risks for lung, and head and neck cancers, Carcinogenesis 2007. [PubMed 17494052]
  2. mammalian microsatellite instability
    Lipkin SM et al. 2000, MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability., Nature genetics. 2000 Jan;24(1):27-35. [PubMed 10615123]

-  MalaCards Disease Associations
  MalaCards Gene Search: MLH3
Diseases sorted by gene-association score: colorectal cancer, hereditary nonpolyposis, type 7* (1200), endometrial cancer* (478), colorectal cancer* (289), colonic benign neoplasm* (163), mlh3-related lynch syndrome* (100), colorectal cancer 7 (21), autosomal dominant disease (7), lynch syndrome (7), early-onset familial alzheimer disease (6)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 6.44 RPKM in Thyroid
Total median expression: 176.17 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -86.54216-0.401 Picture PostScript Text
3' UTR -990.103318-0.298 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR003594 - ATPase-like_ATP-bd
IPR002099 - DNA_mismatch_repair
IPR013507 - DNA_mismatch_repair_C
IPR014762 - DNA_mismatch_repair_CS
IPR014790 - MutL_C
IPR020568 - Ribosomal_S5_D2-typ_fold
IPR014721 - Ribosomal_S5_D2-typ_fold_subgr

Pfam Domains:
PF01119 - DNA mismatch repair protein, C-terminal domain
PF02518 - Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
PF08676 - MutL C terminal dimerisation domain
PF13589 - Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

SCOP Domains:
55874 - ATPase domain of HSP90 chaperone/DNA topoisomerase II/histidine kinase
54211 - Ribosomal protein S5 domain 2-like

ModBase Predicted Comparative 3D Structure on Q9UHC1
FrontTopSide
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologGenome BrowserNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
  Ensembl   
  Protein Sequence   
  Alignment   

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0003682 chromatin binding
GO:0003696 satellite DNA binding
GO:0003697 single-stranded DNA binding
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0016887 ATPase activity
GO:0019237 centromeric DNA binding
GO:0030983 mismatched DNA binding

Biological Process:
GO:0006281 DNA repair
GO:0006298 mismatch repair
GO:0006974 cellular response to DNA damage stimulus
GO:0007130 synaptonemal complex assembly
GO:0007131 reciprocal meiotic recombination
GO:0007140 male meiosis
GO:0007144 female meiosis I
GO:0008104 protein localization

Cellular Component:
GO:0000793 condensed chromosome
GO:0000794 condensed nuclear chromosome
GO:0000795 synaptonemal complex
GO:0001673 male germ cell nucleus
GO:0005634 nucleus
GO:0005712 chiasma
GO:0032300 mismatch repair complex


-  Descriptions from all associated GenBank mRNAs
  BC036866 - Homo sapiens mutL homolog 3 (E. coli), mRNA (cDNA clone IMAGE:5198926), partial cds.
AF195657 - Homo sapiens DNA mismatch repair protein (MLH3) mRNA, complete cds.
AL833875 - Homo sapiens mRNA; cDNA DKFZp762L056 (from clone DKFZp762L056).
L40399 - Homo sapiens (clone S240ii117/zap112) mRNA, complete cds.
BC112167 - Homo sapiens mutL homolog 3 (E. coli), mRNA (cDNA clone MGC:138372 IMAGE:8327635), complete cds.
BC143729 - Homo sapiens cDNA clone IMAGE:9052243, containing frame-shift errors.
AB039667 - Homo sapiens mRNA for DNA mismatch repair protein MLH3, complete cds.
HQ258639 - Synthetic construct Homo sapiens clone IMAGE:100073196 mutL homolog 3 (E. coli) (MLH3) gene, encodes complete protein.
KJ898650 - Synthetic construct Homo sapiens clone ccsbBroadEn_08044 MLH3 gene, encodes complete protein.
KR711731 - Synthetic construct Homo sapiens clone CCSBHm_00028935 MLH3 (MLH3) mRNA, encodes complete protein.
KR711732 - Synthetic construct Homo sapiens clone CCSBHm_00028944 MLH3 (MLH3) mRNA, encodes complete protein.
AK298777 - Homo sapiens cDNA FLJ52020 complete cds, highly similar to DNA mismatch repair protein Mlh3.
JD487579 - Sequence 468603 from Patent EP1572962.
JD155998 - Sequence 137022 from Patent EP1572962.
JD260659 - Sequence 241683 from Patent EP1572962.
JD107904 - Sequence 88928 from Patent EP1572962.
JD157304 - Sequence 138328 from Patent EP1572962.
JD503959 - Sequence 484983 from Patent EP1572962.
JD122375 - Sequence 103399 from Patent EP1572962.
JD536867 - Sequence 517891 from Patent EP1572962.
JD132969 - Sequence 113993 from Patent EP1572962.
JD502106 - Sequence 483130 from Patent EP1572962.
BC012544 - Homo sapiens mutL homolog 3 (E. coli), mRNA (cDNA clone IMAGE:4081607), with apparent retained intron.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa03430 - Mismatch repair

Reactome (by CSHL, EBI, and GO)

Protein Q9UHC1 (Reactome details) participates in the following event(s):

R-HSA-912446 Meiotic recombination
R-HSA-1500620 Meiosis
R-HSA-1474165 Reproduction
R-HSA-1640170 Cell Cycle

-  Other Names for This Gene
  Alternate Gene Symbols: MLH3_HUMAN, NM_001040108, NP_001035197, P49751, Q56DK9, Q9P292, Q9UHC0, Q9UHC1
UCSC ID: uc001xrd.1
RefSeq Accession: NM_001040108
Protein: Q9UHC1 (aka MLH3_HUMAN)
CCDS: CCDS9837.1, CCDS32123.1

-  Gene Model Information
 
category: coding nonsense-mediated-decay: no RNA accession: NM_001040108.1
exon count: 13CDS single in 3' UTR: no RNA size: 7911
ORF size: 4362CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 8823.00frame shift in genome: no % Coverage: 99.81
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.