Alternative titles; symbols
HGNC Approved Gene Symbol: MSH3
Cytogenetic location: 5q14.1 Genomic coordinates (GRCh38): 5:80,654,652-80,876,815 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.1 | Endometrial carcinoma, somatic | 608089 | 3 | |
| Familial adenomatous polyposis 4 | 617100 | Autosomal recessive | 3 |
Fujii and Shimada (1989) identified a gene encoding human homolog of the bacterial mismatch repair protein MutS upstream of the dihydrofolate reductase (DHFR; 126060) gene on chromosome 5q11.2-q13.2. The amino acid sequence encoded by this gene, referred to by them as hMSH3, has 31% identity with that of MutS. In the most conserved region of 156 amino acids in the C-terminal portion, there is more than 50% homology. A similar gene was identified upstream of the mouse DHFR gene (Linton et al., 1989).
The MSH2 gene (609309) and the MSH3 gene were the first 2 mammalian genes with apparent sequence homology to the gene for bacterial mismatch repair protein MutS and were named the human mismatch repair protein 1 (MRP1) and the mouse repair gene 3 (Rep3), respectively, by investigators. (Watanabe et al. (1996) noted that the gene had also been called DUG, for Divergently transcribed Upstream Gene.) Thereafter, a number of MutS-related proteins were isolated in Saccharomyces cerevisiae. Human MutS homolog 2 (MSH2) was named on the basis of sequence similarity to S. cerevisiae MSH2. Human MRP1 and mouse Rep3 are most closely related to yeast MSH3 (Smith et al., 1990) and was thus designated MSH3.
By characterization of cosmid clones, Watanabe et al. (1996) showed that the MSH3 gene consists of 24 exons spanning at least 160 kb. All exon/intron junction sequences matched the classic GT/AG rule, except that intron 6 has AT and AA at the ends. Two major transcripts of 5.0 and 3.8 kb were shown to be derived from the differential use of 2 polyadenylation sites. Expression of this gene and the DHFR gene appear to be regulated by a bidirectional promoter composed of multiple GC boxes and 2 initiator elements.
Fujii and Shimada (1989) identified the MSH3 gene on chromosome 5q11.2-q13.2.
Inokuchi et al. (1995) examined the expression of MSH3 genes in bone marrow cells from 40 patients with various hematologic malignancies. MSH3 mRNA was not detectable in 7 cases, including 3 of chronic myelogenous leukemia, 2 of acute myelogeneous leukemia, 1 of acute lymphocytic leukemia, and 1 of myelodysplastic syndrome. In addition, 17 cases showed significantly reduced expression of the MSH3 gene. Southern blot analysis of genomic DNA demonstrated no remarkable change in the structure and copy number of the MSH3 gene in any case. These results suggested to the authors that inactivation of the MSH3 gene may be involved in the development of hematologic malignancies.
Using PCR, Nakajima et al. (1995) identified a polymorphic 9-bp repeat sequence in exon 1 of the MSH3 gene. Five alleles were observed in unrelated Japanese individuals, with heterozygosity of 0.57.
Familial Adenomatous Polyposis 4
In affected members of 2 unrelated families with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous germline mutations in the MSH3 gene (600887.0001-600887.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Each patient carried a truncating mutation on 1 allele and a splice site mutation on the other allele; all mutations showed loss of function. Normal and adenomatous colonic samples from 1 patient showed complete loss of nuclear MSH3 immunostaining. Tumor tissue from both probands showed high microsatellite instability of di- and tetranucleotides (EMAST). Adenomatous tissue from 1 patient also showed several different somatic mutations in the APC gene (611731).
Endocrine and Other Cancers
Many human tumors show length alterations in repetitive sequence elements. Although this microsatellite instability (MI) has been attributed to mutations in 4 DNA mismatch repair genes in kindreds with hereditary nonpolyposis colorectal cancer (e.g., MSH2, 609309 in HNPCC1, 120435), many sporadic tumors exhibit instability but no detectable mutations in these genes. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Risinger et al. (1996) screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (600393), the human homolog of RTH, and in MSH3. Although they found no FEN mutations, an MSH3 frameshift mutation (600887.0001) was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Risinger et al. (1996) introduced chromosome 5 encoding the MSH3 gene by microcell-mediated chromosome transfer into the mutant cell line and observed an increase in the stability of some, but not all, microsatellites.
Akiyama et al. (1997) screened for somatic mutations of the MSH3 (A)8 repeat in 29 tumors from 23 hereditary nonpolyposis colorectal cancer patients. One or 2 A deletions in the (A)8 repeat were found in 11 (57.9%) of the 19 tumors that showed microsatellite instability but not in 10 MI-negative ones, indicating secondary mutations after germline mutations of other mismatch repair genes. Moreover, the MI frequency of 3 or more nucleotide repeats was higher in MSH3 (A)8-mutated tumor cells than in nonmutated ones. Their data suggested that a mutation of a mismatch repair gene enhances the frequency of another mismatch repair gene mutation, such as of MSH3, resulting in severe microsatellite instability. Yin et al. (1997) came to a similar conclusion: that DNA mismatch repair genes, such as MSH3 and MSH6 (600678), are targets for the mutagenic activity of upstream mismatch repair gene mutations and that this enhanced genomic instability may accelerate the accumulation of mutations in replication/repair error positive tumors.
Marra et al. (1998) presented data that supported and extended the findings of Drummond et al. (1997) and demonstrated that mismatch repair deficiency can arise not only through mutation or transcriptional silencing of a mismatch repair gene, but also as a result of imbalance in the relative amounts of the MSH3 and MSH6 proteins.
De Wind et al. (1999) inactivated the mouse Msh3 and Msh6 genes by targeted disruption. Msh6-deficient mice were prone to cancer. Most animals developed lymphomas or epithelial tumors originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6-deficient background, loss of Msh3 accelerated intestinal tumorigenesis. The frequency of lymphomas was not affected. Furthermore, mismatch-directed antirecombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of mismatch repair functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.
Familial Adenomatous Polyposis 4
In 2 sisters (family 1275) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations in the MSH3 gene: a 1-bp deletion (c.1148delA, NM_002439.4) in exon 7, resulting in a frameshift and premature termination (Lys383ArgfsTer32), and an A-to-C transversion in intron 21 (c.3001-2A-C; 600887.0002), resulting in aberrant splicing and premature termination (Val1001ArgfsTer16) that would alter the dimerization domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, and an in-house database of 2,816 control exomes. The c.1148delA mutation was found at a low frequency (0.008%) in the ExAC database.
Endocrine Cancer, Somatic
In a primary endometrial cancer (608089) and in an endometrial carcinoma cell line, Risinger et al. (1996) found a somatic mutation in the MSH3 gene. The mutation resulted in a truncated product and consisted of a single nucleotide deletion, loss of an A/T basepair at position 1148. This change generated a premature nonsense codon and results in a protein 723 amino acids shorter than the wildtype gene product. No wildtype DNA sequence or gene product was evident in the cell line. Residual wildtype sequence in protein was present in the primary tumor sample, which may have resulted from contaminating normal cells. The mutation was absent in the DNA of normal cells from the patient.
For discussion of the A-to-C transversion in intron 21 (c.3001-2A-C, NM_002439.4) of the MSH3 gene that was found in compound heterozygous state in 2 sibs with familial adenomatous polyposis-4 (FAP4; 617100) by Adam et al. (2016), see 600887.0001.
In 2 sibs (family 1661) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations in the MSH3 gene: a 1-bp deletion (c.2760delC, NM_002439.4) in exon 20, resulting in a frameshift and premature termination (Tyr921MetfsTer36) and a G-to-A transition in intron 16 (c.2319-1G-A; 600887.0004), resulting in aberrant splicing and an in-frame loss of 39 amino acids involved in DNA recognition (Thr774_Glu812del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, and an in-house database of 2,816 control exomes. The c.2760delC mutation was found at a low frequency (0.0016%) in the ExAC database.
For discussion of the G-to-A transition in intron 16 (c.2319-1G-A, NM_002439.4) of the MSH3 gene that was found in compound heterozygous state in 2 sibs with familial adenomatous polyposis-4 (FAP4; 617100) by Adam et al. (2016), see 600887.0003.
Adam, R., Spier, I., Zhao, B., Kloth, M., Marquez, J., Hinrichsen, I., Kirfel, J., Tafazzoli, A., Horpaopan, S., Uhlhaas, S., Stienen, D., Friedrichs, N., and 16 others. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am. J. Hum. Genet. 99: 337-351, 2016. [PubMed: 27476653] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.015]
Akiyama, Y., Tsubouchi, N., Yuasa, Y. Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancer. Biochem. Biophys. Res. Commun. 236: 248-252, 1997. [PubMed: 9240418] [Full Text: https://doi.org/10.1006/bbrc.1997.6942]
de Wind, N., Dekker, M., Claij, N., Jansen, L., van Klink, Y., Radman, M., Riggins, G., van der Valk, M., van't Wout, K., te Riele, H. HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nature Genet. 23: 359-362, 1999. [PubMed: 10545954] [Full Text: https://doi.org/10.1038/15544]
Drummond, J. T., Genschel, J., Wolf, E., Modrich, P. DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutS-alpha/hMutS-beta ratio and reduces the efficiency of base-base mismatch repair. Proc. Nat. Acad. Sci. 94: 10144-10149, 1997. [PubMed: 9294177] [Full Text: https://doi.org/10.1073/pnas.94.19.10144]
Fujii, H., Shimada, T. Isolation and characterization of cDNA clones derived from the divergently transcribed gene in the region upstream from the human dihydrofolate reductase gene. J. Biol. Chem. 264: 10057-10064, 1989. [PubMed: 2722860]
Inokuchi, K., Ikejima, M., Watanabe, A., Nakajima, E., Orimo, H., Nomura, T., Shimada, T. Loss of expression of the human MSH3 gene in hematological malignancies. Biochem. Biophys. Res. Commun. 214: 171-179, 1995. [PubMed: 7669036] [Full Text: https://doi.org/10.1006/bbrc.1995.2271]
Linton, J. P., Yen, J. Y.-J., Selby, E., Chen, Z., Chinsky, J. M., Liu, K., Kellems, R. E., Crouse, G. F. Dual bidirectional promoters at the mouse dhfr locus: cloning and characterization of two mRNA classes of the divergently transcribed Rep-1 gene. Molec. Cell. Biol. 9: 3058-3072, 1989. [PubMed: 2674679] [Full Text: https://doi.org/10.1128/mcb.9.7.3058-3072.1989]
Marra, G., Iaccarino, I., Lettieri, T., Roscilli, G., Delmastro, P., Jiricny, J. Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proc. Nat. Acad. Sci. 95: 8568-8573, 1998. [PubMed: 9671718] [Full Text: https://doi.org/10.1073/pnas.95.15.8568]
Nakajima, E., Orimo, H., Ikejima, M., Shimada, T. Nine-bp repeat polymorphism in exon 1 of the hMSH3 gene. Jpn. J. Hum. Genet. 40: 343-345, 1995. [PubMed: 8851770] [Full Text: https://doi.org/10.1007/BF01900603]
Risinger, J. I., Umar, A., Boyd, J., Berchuck, A., Kunkel, T. A., Barrett, J. C. Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nature Genet. 14: 102-109, 1996. [PubMed: 8782829] [Full Text: https://doi.org/10.1038/ng0996-102]
Smith, M. L., Mitchell, P. J., Crouse, G. F. Analysis of the mouse Dhfr/Rep-3 major promoter region by using linker-scanning and internal deletion mutations and DNase I footprinting. Molec. Cell. Biol. 10: 6003-6012, 1990. [PubMed: 2233729] [Full Text: https://doi.org/10.1128/mcb.10.11.6003-6012.1990]
Watanabe, A., Ikejima, M., Suzuki, N., Shimada, T. Genomic organization and expression of the human MSH3 gene. Genomics 31: 311-318, 1996. [PubMed: 8838312] [Full Text: https://doi.org/10.1006/geno.1996.0053]
Yin, J., Kong, D., Wang, S., Zou, T.-T., Souza, R. F., Smolinski, K. N., Lynch, P. M., Hamilton, S. R., Sugimura, H., Powell, S. M., Young, J., Abraham, J. M., Meltzer, S. J. Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas. Hum. Mutat. 10: 474-478, 1997. [PubMed: 9401011] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:6<474::AID-HUMU9>3.0.CO;2-D]