MSH2 (human mutS homolog 2)

2005-07-01   Enric Domingo , Sim Schwartz Jr 

Oncologia Molecular i Envelliment, Centre dInvestigacions en Bioqumica i Biologia Molecular (CIBBIM) Hospital Universitari Vall dHebron Passeig Vall dHebron 119-129 Barcelona 08035, Catalonia, Spain

Identity

HGNC
LOCATION
2p21
LOCUSID
ALIAS
COCA1,FCC1,HNPCC,HNPCC1,LCFS2,MMRCS2,hMSH2
FUSION GENES

DNA/RNA

Atlas Image
Diagram of the MSH2 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.

Description

The MSH2 gene is composed of 16 exons spanning in a region of 80098 bp.

Transcription

The transcribed mRNA has 3145 bp.

Proteins

Atlas Image
Diagram of the MSH2 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The boxes inside represent the DNA binding domain (red), the hMSH3/hMSH6 interaction domain (yellow) and the MutL homologs interaction domain (green); C: Carboxyl-terminal; N: Amino-terminal.

Description

Aminoacids: 934. Molecular Weight: 104.7 kDa. MSH2 is a protein involved in the mismatch repair process after DNA replication. It contains a DNA binding domain and two interaction domains, one for MSH3 or MSH6 and the other for MutL homologs (MLH1 and PMS2), located in two different regions of the gene.

Localisation

Nuclear

Function

MSH2 can bind to MSH6 or to MSH3 to form the MutS alpha or the MutS beta complexes respectively. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Upon binding to the mismatch, the MutS complex associates with the MutL complex (composed of MLH1 and PMS2), and recruits the proteins needed for DNA excision and repair. (See also: Repair of DNA double-strand breaks

Homology

MSH2 is homologue to the bacterial MutS gene and MSH2 homologues are also present in eukaryotes.

Mutations

Germinal

There are over 300 MSH2 germline mutations described along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). Mutations do not occur in any particular hotspot or region of the gene and include either nucleotide substitutions (missense, nonsense and splicing errors) and insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. Although rare there are described some founding mutations which account for a high proportion of the HNPCC tumours in some specific populations. Some germline genetic changes have also been described in exons and introns as non pathogenic.

Somatic

Some sporadic mismatch repair deficient cases (sporadic MSI) with somatic MSH2 mutations are described.

Implicated in

Entity name
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
MSH2 mutations in HNPCC account for about 25% of the total cases approximately. These 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 also been described that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumour diagnosis.
Entity name
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 has a lower incidence in some other tissues.
Prognosis
MSI tumours have better prognosis than the MicroSatellite Stable (MSS).
Oncogenesis
Few sporadic cases and about 25% of the HNPCC are due to different mutations in MSH2. These mutations are germline in HNPCC.
Entity name
Muir-Torre syndrome
Disease
Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy.
Oncogenesis
Muir-Torre syndrome is mainly due to inherited MSH2 mutations.

Bibliography

Pubmed IDLast YearTitleAuthors
155635102005Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.Alazzouzi H et al
76963681995Microsatellite instability in inherited and sporadic neoplasms.Eshleman JR et al
82526161993The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.Fishel R et al
119008752002DNA mismatch repair defects: role in colorectal carcinogenesis.Jacob S et al
148719152004A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.Lynch HT et al
152350302004A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.Mangold E et al
119206792002DNA mismatch repair and mutation avoidance pathways.Marti TM et al
124197612002Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.Mitchell RJ et al

Other Information

Locus ID:

NCBI: 4436
MIM: 609309
HGNC: 7325
Ensembl: ENSG00000095002

Variants:

dbSNP: 4436
ClinVar: 4436
TCGA: ENSG00000095002
COSMIC: MSH2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000095002ENST00000233146P43246
ENSG00000095002ENST00000406134E9PHA6
ENSG00000095002ENST00000543555P43246
ENSG00000095002ENST00000644092A0A2R8Y7S8
ENSG00000095002ENST00000644900A0A2R8Y713
ENSG00000095002ENST00000645339A0A2R8YFH0
ENSG00000095002ENST00000645506A0A2R8Y6P0
ENSG00000095002ENST00000646415A0A2R8YG02

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
Mismatch repairKEGGko03430
Colorectal cancerKEGGko05210
Mismatch repairKEGGhsa03430
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
DNA RepairREACTOMER-HSA-73894
Mismatch RepairREACTOMER-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)REACTOMER-HSA-5358565
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)REACTOMER-HSA-5358606
TP53 Regulates Transcription of DNA Repair GenesREACTOMER-HSA-6796648
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443761Colorectal Neoplasms, Hereditary NonpolyposisDiseaseLiterature, MultilinkAnnotationassociated23788249

References

Pubmed IDYearTitleCitations
216426822011Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.198
190989122009Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1.189
168853852006Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.149
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
210789762010MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2).132
168074122006Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.108
196223572009Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome.101
223319442012Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.95
153426962004BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.85

Citation

Enric Domingo ; Sim Schwartz Jr

MSH2 (human mutS homolog 2)

Atlas Genet Cytogenet Oncol Haematol. 2005-07-01

Online version: http://atlasgeneticsoncology.org/gene/340/msh2