MSH2（humanmutShomolog2）

Atlas of Genetics and Cytogenetics in Oncology and Haematology
MSH2 (human mutS homolog 2)
Identity
Other
COCA1
names
FCC1
hMSH2
HNPCC1
Hugo MSH2
Location2p22-p21
Between the FLJ40172 and MSH6 genes.
DNA/RNA
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.
Protein
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 HNPCC (Hereditary Non Polyposis Colorectal Cancer)
Disease Predisposition to develop cancer, preferentially colorectal, but also in endometrium, , 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 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 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.
External links
Nomenclature
Hugo MSH2
GDB MSH2
Entrez_Gene MSH2 4436 mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
Cards
GeneCards MSH2
Ensembl MSH2
CancerGene MSH2
Genatlas MSH2
GeneLynx MSH2
eGenome MSH2
euGene4436
Genomic and cartography
GoldenPath MSH2 - chr2:47541914-47622011 + 2p21 (hg17-May_2004) Ensembl MSH2 - 2p21 [CytoView]
NCBI Genes Cyto Gene Seq[Map View - NCBI]
OMIM Disease map [OMIM]
HomoloGene MSH2
Gene and transcription
Genbank AF066081 [ SRS ]AF066081[ ENTREZ ]
Genbank AY344477 [ SRS ]AY344477[ ENTREZ ]
Genbank AY601851 [ SRS ]AY601851[ ENTREZ ]
Genbank U41221 [ SRS ]U41221[ ENTREZ ]
Genbank BC001122 [ SRS ]BC001122[ ENTREZ ]
RefSeq NM_000251 [ SRS ]NM_000251[ ENTREZ ]
RefSeq NT_086610 [ SRS ]NT_086610[ ENTREZ ]
AceView MSH2 AceView - NCBI
TRASER MSH2 Traser - Stanford
Unigene Hs.156519 [ SRS ]Hs.156519[ NCBI ] HS156519[ spliceNest ] Protein : pattern, domain, 3D structure
SwissProt P43246 [ SRS]P43246[ EXPASY ]P43246[ INTERPRO ]
Prosite PS00486 DNA_MISMATCH_REPAIR_2[ SRS ]PS00486 DNA_MISMATCH_REPAIR_2[ Expasy ]
Interpro IPR011184 MSH2[ SRS ]IPR011184 MSH2[ EBI ]
Interpro IPR000432 MutS_C[ SRS ]IPR000432 MutS_C[ EBI ]
Interpro IPR007860 MutS_II[ SRS ]IPR007860 MutS_II[ EBI ]
Interpro IPR007696 MutS_III[ SRS ]IPR007696 MutS_III[ EBI ]
Interpro IPR007861 MutS_IV[ SRS ]IPR007861 MutS_IV[ EBI ]
Interpro IPR007695 MutS_N[ SRS ]IPR007695 MutS_N[ EBI ]
CluSTr P43246
Pfam PF01624 MutS_I[ SRS ]PF01624 MutS_I[ Sanger ]pfam01624[ NCBI-CDD ]
Pfam PF05188 MutS_II[ SRS ]PF05188 MutS_II[ Sanger ]pfam05188[ NCBI-CDD ]
Pfam PF05192 MutS_III[ SRS ]PF05192 MutS_III[ Sanger ]pfam05192[ NCBI-CDD ]
Pfam PF05190 MutS_IV[ SRS ]PF05190 MutS_IV[ Sanger ]pfam05190[ NCBI-CDD ]
Pfam PF00488 MutS_V[ SRS ]PF00488 MutS_V[ Sanger ]pfam00488[ NCBI-CDD ]
Prodom PD001263 MutS_C[INRA-Toulouse]
Prodom P43246 MSH2_HUMAN [ Domain structure ]P43246 MSH2_HUMAN [ sequences sharing at least 1 domain ]
Blocks P43246
Polymorphism : SNP, mutations, diseases
OMIM120435[ map ]
GENECLINICS120435
SNP MSH2 [dbSNP-NCBI]
SNP NM_000251 [SNP-NCI]
SNP MSH2 [GeneSNPs - Utah]MSH2 [SNP - CSHL]MSH2] [HGBASE - SRS]
General knowledge
Family
Browser
MSH2 [UCSC Family Browser]
SOURCE NM_000251
SMD Hs.156519
SAGE Hs.156519
Amigo function|ATP binding
Amigo function|damaged DNA binding
Amigo process|mismatch repair
Amigo process|negative regulation of cell cycle
Amigo component|nucleus
Amigo process|postreplication repair
PubGene MSH2
Other databases
Probes
Probe MSH2 Related clones (RZPD - Berlin)
PubMed
PubMed77 Pubmed reference(s) in LocusLink
Bibliography
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R.
Cell 1993; 75: 1027-1038.
Medline 8252616
Microsatellite instability in inherited and sporadic neoplasms.
Eshleman JR, Markowitz SD.
Curr Opin Oncol 1995; 7: 83-89. (REVIEW).
Medline 7696368
DNA mismatch repair defects: role in colorectal carcinogenesis.
Jacob S, Praz F.
Biochimie 2002; 84: 27-47. (REVIEW)
Medline 11900875
DNA mismatch repair and mutation avoidance pathways.
Marti TM, Kunz C, Fleck O.
Medline 11920679
Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H.
Am J Epidemiol 2002; 156: 885-902. (REVIEW).
Medline 12419761
A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.
Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Wagner A, Fodde R, de la ChapelleA.
JAMA 2004; 291: 718-724.
Medline 14871915
A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.
Mangold E, Pagenstecher C, Leister M, Mathiak M, Rutten A, Friedl W, Propping P, Ruzicka T, Kruse R.
J Med Genet 2004; 41: 567-572.
Medline 15235030
Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.
Alazzouzi H, Domingo E, Gonzalez S, Blanco I, Armengol M, Espin E, Plaja A, Schwartz S, Capella G, Schwartz S Jr.
Hum Mol Genet 2005; 14: 235-239.
Medline 15563510
REVIEW articles automatic search in PubMed
Last year
automatic search in PubMed
publications
BiblioGene - INIST
Contributor(s)
Written07-
Enric Domingo, Sim¢ Schwartz Jr
2005
Citation
This paper should be referenced as such :
Domingo E, Schwartz S Jr . MSH2 (human mutS homolog 2). Atlas Genet Cytogenet Oncol Haematol. July 2005 .
URL : biogen.fr/services/chromcancer/Genes/MSH2ID340ch2p22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology。