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
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
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.
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.
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.
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
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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.