MLH1, MSH2 and MSH6
MLH1
In
databases:
● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery):
4292 or MLH1
● Ensembl (http://www.ensembl.org/index.html):
ENSG00000076242
● GeneCards (http://www.genecards.org/): MLH1
● HGNC (http://www.genenames.org/): 7127 or MLH1
Gene locus:
3p21.3
Protein name:
MutL homolog 1, colon cancer, nonpolyposis
type 2 (E. coli)
Protein Size:
756 amino acids; about 85 kDa
MSH2
In
databases:
● Ensembl (http://www.ensembl.org/index.html):
ENSG00000095002
● GeneCards (http://www.genecards.org/): MSH2
● HGNC (http://www.genenames.org/): 7325 or MSH2
Gene locus:
2p22-p21
Protein name:
MutS homolog 2, colon cancer, nonpolyposis
type 1 (E. coli)
Protein Size:
934 amino acids; about 105 kDa
MSH6
In
databases:
Ensembl (http://www.ensembl.org/index.html):
ENSG00000116062
GeneCards (http://www.genecards.org/): MSH6
HGNC (http://www.genenames.org/): 7329 or MSH6
Gene locus:
2p16
Protein name:
MutS homolog 6 (E. coli)
Protein Size:
1360 amino acids; about 153 kDa
Function:
MLH1 forms heterodimer with PMS2 (MutL
alpha), PMS1 (MutL beta) or MLH3 (MutL gamma). MutL alpha is a component of the
post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha
(MSH2-MSH6) or MutS beta (MSH2-MSH6), which recognize and bind to a dsDNA
mismatch, then MutL alpha is recruited to the heteroduplex. While MutS alpha
complex binds to base-base and insertion-deletion mismatches, MutS beta only
binds to insertion-deletion mismatches. Assembly of the MutL-MutS-heteroduplex
ternary complex in presence of RFC (replication factor C) and PCNA
(Proliferating Cell Nuclear Antigen) is sufficient to activate endonuclease
activity of PMS2 (it seems that MLH1 itself has no enzymatic activity). It
introduces single-strand breaks near the mismatch and thus generates new entry
points for the exonuclease EXO1 to degrade the strand containing the mismatch.
DNA methylation would prevent cleavage and therefore assure that only the newly
mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts
physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit
the DNA polymerase III to the site of the MMR. In fact, MutL alpha is thought
to be responsible for directing the downstream MMR events, including strand
discrimination, excision, and resynthesis. Also implicated in DNA damage
signaling, a process which induces cell cycle arrest and can lead to apoptosis
in case of major DNA damages.
MLH1, MSH2 and MSH6 are part of the
BRCA1-associated genome surveillance complex (BASC), which contains BRCA1,
MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This
association could be a dynamic process changing throughout the cell cycle and
within subnuclear domains.
Cancer-related alterations
Germinal
mutations: there are over 300 MLH1 and 300 MSH2 germline mutations described
all along the gene that cause HNPCC. These mutations are not present in any
particular hot spot or zone of the gene and include either nucleotide
substitutions (missense, nonsense or splicing errors) or insertions/deletions
(gross or small). In most of these mutations the resulting protein is
truncated. There are also founding mutations which account for a high
proportion of the HNPCC tumors in some specific populations (for example there
are two Finnish mutations that delete the exons 16 or 6). Regarding MSH6, its
germline mutations have variable penetration and are relatively rare in HNPCC
and HNPCC-like families.
Somatic ML1, MSH2 and MSH6 mutations have
been observed mainly in tumors of large intestine, stomach, ovary and
endometrium. These mutations are not present in any particular hot spot or zone
of the gene and include either nucleotide substitutions (missense, nonsense or
splicing errors) or insertions/deletions (gross or small). Somatic MLH1 and
MSH2 mutation may cause microsatellite instability (MSI) in colorectal, gastric
and endometrial cancer. The involvement of somatic or epigenetic inactivation
of MSH6 is rare in colorectal cancer and missense mutations in MSH6 are often
clinically innocuous or have a low penetrance. However, somatic mutations of
MSH6 have been shown to confer resistance to alkylating agents such as
temozolomide in malignant gliomas in vivo.
Defects in MLH1, MSH2 and MSH6 are the
cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2), HNPCC1
(and HNPCC8, see below) and HNPCC5, respectively. Mutations in more than one
gene locus can be involved alone or in combination in the production of the
HNPCC phenotype (also called Lynch syndrome). Most families with clinically
recognized HNPCC have mutations in either MLH1 or MSH2 genes (25% of cases
each). HNPCC is an autosomal, dominantly inherited disease associated with
marked increase in cancer susceptibility. It is characterized by a familial
predisposition to early onset colorectal carcinoma (CRC) and extra-colonic
cancers of the gastrointestinal, urological and female reproductive tracts.
HNPCC is reported to be the most common form of inherited colorectal cancer in
the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC
originate within benign neoplastic polyps termed adenomas.
Clinically, HNPCC is often divided into
two subgroups.
Type I: hereditary predisposition to
colorectal cancer, a young age of onset, and carcinoma observed in the proximal
colon.
Type II: patients have an increased risk
for cancers in certain tissues such as the uterus, ovary, breast, stomach,
small intestine, skin, and larynx in addition to the colon. Diagnosis of
classical HNPCC is based on the Amsterdam
3 or more relatives affected by colorectal
cancer, one a first degree relative of the other two;
2 or more generation affected;
1 or more colorectal cancers presenting
before 50 years of age; exclusion of hereditary polyposis syndromes.
MSH6 mutations (10% of HNPCC cases) appear
to be associated with atypical HNPCC and in particular with development of
endometrial carcinoma or atypical endometrial hyperplasia, the presumed
precursor of endometrial cancer. Defects in MSH6 are also found in familial
colorectal cancers (suspected or incomplete HNPCC) that do not fulfill the Amsterdam
Defects in MSH2 are a cause of a
particular type of HNPCC named HNPCC8, resulting from heterozygous deletion of
3-prime exons of EPCAM and intergenic regions directly upstream of MSH2; the
consequence is a read-through and epigenetic silencing of MSH2 in tissues
expressing EPCAM.
MicroSatellite Instability (MSI) is a
characteristic of tumors in which the molecular feature that leads to cancer is
the lost of the mismatch repair (MMR) system. This phenotype is present in 15%
of colorectal, gastric and endometrial cancer, and with lower incidence in some
other tissues.
MSI may be due to sporadic or germline (in
HNPCC) mutations in MLH1 or MSH2.
Germline alterations in MLH1 or MSH2 are a
cause of Muir-Torre syndrome (MuToS); also abbreviated MTS. MuToS is a rare
autosomal dominant disorder characterized by sebaceous neoplasms and visceral
malignancy.
Defects in MLH1 or MSH6 are a cause of
mismatch repair cancer syndrome (MMRCS) MMRCS is an autosomal dominant disorder
characterized by malignant tumors of the brain associated with multiple
colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and
cafe au lait spots. MSH2 mutations may predispose to hematological malignancies
and multiple cafe-au-laity spots.
References (open access):
Lynch Syndrome. Kohlmann W, Gruber SB. In:
Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet].
Seattle (WA): University of Washington, Seattle; 1993-2004 Feb 05 [updated 2011 Aug
11].
An optimized pentaplex PCR for detecting
DNA mismatch repair-deficient colorectal cancers. Goel A, Nagasaka T, Hamelin
R, Boland CR. PLoS One. 2010 Feb 24;5(2):e9393.
Cancer risk in MLH1, MSH2 and MSH6
mutation carriers; different risk profiles may influence clinical management. Ramsoekh
D, Wagner A, van Leerdam ME, Dooijes D, Tops CM, Steyerberg EW, Kuipers EJ. Hered
Cancer Clin Pract. 2009 Dec 23;7(1):17.
A comparison of models used to predict
MLH1, MSH2 and MSH6 mutation carriers. Pouchet CJ, Wong N, Chong G, Sheehan MJ,
Schneider G, Rosen-Sheidley B, Foulkes W, Tischkowitz M. Ann Oncol. 2009
Apr;20(4):681-8.
The frequency of Muir-Torre syndrome among
Lynch syndrome families. South CD, Hampel H, Comeras I, Westman JA, Frankel WL,
de la Chapelle A.
J Natl Cancer Inst. 2008 Feb 20;100(4):277-81.
Lynch syndrome (hereditary nonpolyposis
colorectal cancer) diagnostics. Lagerstedt Robinson K, Liu T, Vandrovcova J,
Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein
B, Peltomäki P, Kolodner RD, Nilbert M, Lindblom A. J Natl Cancer Inst. 2007
Feb 21;99(4):291-9.
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