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| | 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 |
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| 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) |
| 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. |
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| 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. |
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| 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). |
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| Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. |
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