Alt. symbols: GTBP

Approved name: mutS homolog 6
Alt. names: mutS (E. coli) homolog 6, mutS homolog 6 (E. coli)

Location: 2p16.3: 47695530 - 47810063 (+)
Gene type: protein_coding, 26 transcripts.

Scores: LoFtool: 0.021200 | pLI: 0.00003670 | LOEUF: 0.498

HGNC: 7329

NCBI: 2956, RefSeq: NG_007111.1

Ensembl: ENSG00000116062.19

LRG_219 | Status: public

OMIM: 600678

Expression | ProteinAtlas

The MSH6 gene encodes a member of the post-replicative DNA mismatch repair (MMR) family of proteins. The MSH6 protein dimerizes with MSH2 to form the MutS alpha heterodimer, which identifies and binds to DNA regions where mismatch errors have been made during replication. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. Binding to mismatched DNA provokes an ADP to ATP exchange, resulting in a conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone, which is crucial for mismatch repair. After binding, either MutS complex can recruit and complex with the MutL alpha heterodimer, which initiates downstream MMR events, including strand discrimination, excision, and resynthesis. DNA helicase MCM9 is also recruited to chromatin to unwind mismatch-containing DNA strands (PMID: 26300262). MutS alpha may also play a role in homologous recombination (HR)-mediated repair.

Monoallelic MSH6 mutations are associated with an autosomal dominant incompletely penetrant hereditary cancer predisposition syndrome called hereditary nonpolyposis colorectal cancer type 5 (HNPCC5) [OMIM: 614350], characterized by the onset of colorectal cancer and/or extracolonic cancers, particularly endometrial cancer, usually in mid-adulthood. Monoallelic somatic and germline mutations have also been associated with sporadic and familial endometrial cancer [OMIM: 608089]. Biallelic MSH6 los s-of-function leads to a rare and severe autosomal recessive childhood cancer predisposition syndrome characterized by hematologic malignancy, brain tumors, and gastrointestinal (GI) tumors called Mismatch repair cancer syndrome type 3 [OMIM: 619097]. Multiple cafe-au-lait spots, axillary freckling, and Lisch nodules reminiscent of neurofibromatosis type 1 may also be present and microsatellite instability is often detected in tumor samples. MMR gene deficiencies - and particularly that of MSH6 - has been associated with selective IgA deficiency, common variable immunodeficiency (CVID), and even a hyper-IgM-like antibody deficiency phenotype via roles in both class switch recombination and somatic hypermutation (PMID: 16283678, 17259933, 18824584, 22250089). [Load More]