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MSH2 (human mutS homolog 2)
Enric Domingo, Simó Schwartz Jr
Oncologia Molecular i Envelliment, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM)
Hospital Universitari Vall d'Hebron Passeig Vall d'Hebron 119-129 Barcelona 08035, Catalonia, Spain (ED,
SSJr)
Published in Atlas Database: July 2005
Online updated version: http://AtlasGeneticsOncology.org/Genes/MSH2ID340ch2p22.html
DOI: 10.4267/2042/38240
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: COCA1; FCC1; hMSH2; HNPCC1
HGNC (Hugo): MSH2
Location: 2p22-p21
Local order: Between the FLJ40172 and MSH6 genes.
Localisation
DNA/RNA
Nuclear.
Description
Function
The MSH2 gene is composed of 16 exons spanning in a
region of 80098 bp.
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.
Transcription
The transcribed mRNA has 3145 bp.
Protein
Description
Aminoacids: 934. Molecular Weight: 104.7 kDa.
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.
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
292
MSH2 (human mutS homolog 2)
Domingo E, Schwartz S Jr
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.
Homology
MSI (MicroSatellite Instability)
MSH2 is homologue to the bacterial MutS gene and
MSH2 homologues are also present in eukaryotes.
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.
Mutations
Germinal
There are over 300 MSH2 germline mutations
described along the gene that causes hereditary nonpolyposis 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.
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.
Somatic
Some sporadic mismatch repair deficient cases
(sporadic MSI) with somatic MSH2 mutations are
described.
Implicated in
References
HNPCC (Hereditary Non Polyposis
Colorectal Cancer)
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA,
Garber J, Kane M, Kolodner R. The human mutator gene
homolog MSH2 and its association with hereditary
nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027-38
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
these 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.
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
Eshleman JR, Markowitz SD. Microsatellite instability in
inherited and sporadic neoplasms. Curr Opin Oncol. 1995
Jan;7(1):83-9
Jacob S, Praz F. DNA mismatch repair defects: role in
colorectal carcinogenesis. Biochimie. 2002 Jan;84(1):27-47
Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation
avoidance pathways. J Cell Physiol. 2002 Apr;191(1):28-41
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H.
Mismatch repair genes hMLH1 and hMSH2 and colorectal
cancer: a HuGE review. Am J Epidemiol. 2002 Nov
15;156(10):885-902
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 Chapelle A. A founder mutation of
the MSH2 gene and hereditary nonpolyposis colorectal cancer
in the United States. JAMA. 2004 Feb 11;291(6):718-24
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MSH2 (human mutS homolog 2)
Domingo E, Schwartz S Jr
Mangold E, Pagenstecher C, Leister M, Mathiak M, Rütten A,
Friedl W, Propping P, Ruzicka T, Kruse R. A genotypephenotype correlation in HNPCC: strong predominance of
msh2 mutations in 41 patients with Muir-Torre syndrome. J
Med Genet. 2004 Jul;41(7):567-72
levels of microsatellite instability characterize MLH1 and MSH2
HNPCC carriers before tumor diagnosis. Hum Mol Genet. 2005
Jan 15;14(2):235-9
Alazzouzi H, Domingo E, González S, Blanco I, Armengol M,
Espín E, Plaja A, Schwartz S, Capella G, Schwartz S Jr. Low
Domingo E, Schwartz S Jr. MSH2 (human mutS homolog 2).
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4):292-294.
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(4)
This article should be referenced as such:
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