Alternative titles; symbols
HGNC Approved Gene Symbol: MUTYH
SNOMEDCT: 254878006;
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38): 1:45,329,242-45,340,440 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Adenomas, multiple colorectal | 608456 | Autosomal recessive | 3 |
| Gastric cancer, somatic | 613659 | 3 |
Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation, and other byproducts of cellular metabolism. MUTYH is a BER DNA glycosylase that helps protect cells against the mutagenic effects of guanine oxidation (summary by Cheadle and Sampson, 2003).
The E. coli mutY and mutM (OGG1; 601982) glycosylases work together to prevent mutations from certain types of oxidative damage, in particular the oxidized guanine lesion 8-oxodG. To identify sequences encoding proteins homologous to E. mutY, Slupska et al. (1996) screened a human cDNA sequence database. They identified an EST which was then used to probe a human BAC library to isolate genomic human mutY, which they referred to as MYH, also symbolized MUTYH. They also isolated a full-length cDNA clone from a human brain tissue cDNA library. The gene encodes a 535-amino acid protein with 41% identity to E. coli mutY.
Lu and Fawcett (1998) isolated a full-length Schizosaccharomyces pombe MYH cDNA. The cDNA encodes a 461-amino acid protein that shares 31% amino acid identity with human MYH and 28% identity with E. coli mutY.
Slupska et al. (1996) determined that the human MUTYH gene has 16 exons and encompasses 7.1 kb.
By fluorescence in situ hybridization analysis using the human MUTYH genomic clone, Slupska et al. (1996) mapped the MUTYH gene to chromosome 1p34.3-1p32.1.
McGoldrick et al. (1995) identified an A/G mismatch-nicking endonuclease, MYH, in nuclear extracts from calf thymus and human HeLa cells. Western blot analysis using antibodies against the E. coli mutY protein detected a 65-kD band in calf and HeLa cell nuclear extracts. Preincubation of calf thymus nuclear extracts with E. coli anti-mutY antibody decreased the A/G nicking activity in a dose-dependent manner. Calf MYH has both nicking and glycosylase activity and is active at A/G, A/GO, and A/C mismatches, showing specificity similar to that of E. coli mutY.
Lu and Fawcett (1998) found that recombinant S. pombe MYH has glycosylase and nicking activities and is active at A/G and A/GO sites, similar to E. coli mutY.
By examining gene expression profiles, Fry et al. (2008) showed that elevated MYH expression was associated with increased sensitivity to MNNG, a DNA alkylating agent. Knockdown of MYH expression reduced the sensitivity of a human lymphoblast cell line to MNNG-induced cell killing. Furthermore, Myh -/- mouse embryonic fibroblasts were much less sensitive than wildtype fibroblasts to MNNG-induced cell killing. Analysis of genes that were differentially expressed between cell lines with the highest and lowest MNNG sensitivities integrated MYH into a protein network related to human cancer and tumorigenesis.
Crystal Structure
Fromme et al. (2004) reported the use of disulfide crosslinking to obtain high resolution crystal structures of MutY-DNA lesion-recognition complexes. These structures revealed the basis for recognizing both lesions in the A-oxoG pair and for catalyzing removal of the adenine base.
Familial Adenomatous Polyposis 2
Al-Tassan et al. (2002) stated that inherited defects of base excision repair had not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in E. coli base excision repair, lead to increased transversions of G:C to T:A (Nghiem et al., 1988; Thomas et al., 1997). Al-Tassan et al. (2002) studied a British family in which 3 sibs were affected with familial adenomatous polyposis-2 (FAP2; 608456). There was no clear pathogenic change in the APC gene (611731). They showed that 11 tumors from the 3 affected sibs contained 18 somatic inactivating mutations of APC and that 15 of these mutations were G:C-T:A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the sibs were compound heterozygous for the nonconservative missense variants tyr165-to-cys (Y165C; 604933.0001) and gly382-to-asp (G382D; 604933.0002). These mutations affect residues that are conserved in mutY of E. coli. Tyrosine-82 is located in the pseudo-helix-hairpin-helix motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the tyr82-to-cys and gly253-to-asp mutant proteins with 8-oxoG:A and G:A substrates showed that their activity was reduced significantly. The findings linked the inherited variants in MYH to the pattern of somatic APC mutation in the British family and implicated defective base excision repair in predisposition to tumors in humans.
Jones et al. (2002) tested 21 patients in the United Kingdom who had multiple colonic adenomas and found biallelic MYH mutations in 7, all of whom were of Welsh, Indian, or Pakistani origin. They found that patients with origins on the Indian subcontinent carried 1 of 2 novel nonsense mutations (604933.0004-604933.0005).
Sieber et al. (2003) screened for germline MYH mutations in 152 patients with multiple (3 to 100) colorectal adenomas and 107 APC mutation-negative probands with classic familial adenomatous polyposis (more than 100 adenomas). Six patients with multiple adenomas and 8 patients with polyposis had biallelic MYH variants. Missense and protein-truncating mutations were found, and the spectrum of mutations was very similar in the 2 groups of patients. In the tumors of carriers of biallelic mutations, all somatic APC mutations were G:C-T:A transversions. In the group with multiple adenomas, approximately one-third of patients with more than 15 adenomas had biallelic MYH mutations. In the polyposis group, no patient with biallelic MYH mutations had severe disease (more than 1,000 adenomas), but 3 had extracolonic disease (2 had duodenal polyposis and 1 had congenital hypertrophy of the retinal pigment epithelium). No desmoid tumors were reported. Mutation analysis was also performed on the MTH1 (600312) and OGG1 genes, but no clearly pathogenic mutations were identified.
Marra and Jiricny (2003) commented on the remarkable fact that of the 36 germline mutations identified in biallelic configurations in white European patients in the studies of Al-Tassan et al. (2002), Jones et al. (2002), and Sieber et al. (2003), 31 (86%) resulted in the amino acid substitutions Y165C and G382D, and 14 of 18 patients with these substitutions (78%) had either a homozygous or compound heterozygous configuration. Marra and Jiricny (2003) also diagrammed the repair of mutations involving 8-oxoguanine in human cells by the proteins MTH1, OGG1, and MYH.
Among 614 families recorded in 6 regional registers of polyposis in the U.K., Sampson et al. (2003) identified 111 with neither dominant transmission nor evidence of APC mutation. Molecular genetic analysis showed that 25 had biallelic mutations of the MYH gene. The data showed that MYH polyposis can be transmitted as an autosomal recessive trait, requiring a change in genetic counseling, testing, and surveillance. Sampson et al. (2003) recommended that genetic analysis of MYH should be offered to patients with a phenotype resembling familial adenomatous polyposis (FAP) or attenuated FAP, when no clear evidence of vertical transmission is recorded.
Baglioni et al. (2005) reported 2 sibs, born from consanguineous parents, who were found to be homozygous for a frameshift mutation in the MYH gene (604933.0008). The propositus presented with a low number of colonic lesions and an early-onset colorectal cancer. Both sibs had a childhood history of pilomatricomas (132600), which are benign tumors derived from hair follicles. Pilomatricomas have been associated with mutation in the CTNNB1 gene (116806), which is the site of mutations that predispose to colorectal cancer.
Farrington et al. (2005) presented a large, systematically collected population-based association study (2,239 cases; 1,845 controls) that explored the contribution to colorectal cancer incidence of inherited defects in base-excision repair (BER) genes. They showed that biallelic MUTYH defects impart a 93-fold excess risk of colorectal cancer, which accounted for 0.8% of cases aged less than 55 years and 0.54% of the entire cohort. Penetrance of homozygous carriers was almost complete by age 60 years. Significantly more biallelic carriers had coexisting adenomatous polyps. However, notably, 36% of biallelic carriers had no polyps. Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes: OGG1 (601982) and MTH1 (600312). Recessive inheritance accounted for the elevated risk for those aged less than 55 years. However, there was also a 1.68-fold excess risk for heterozygous carriers aged more than 55 years, with a population attributable risk in this age group of 0.93%. These data provided strong evidence for a causative role of BER defects in colorectal cancer etiology and showed that heterozygous MUTYH mutations predispose to colorectal cancer later in life. These findings, the authors suggested, have clinical relevance for BER gene testing for patients with colorectal cancer and for genetic counseling of their relatives.
Webb et al. (2006) stated that they believed that the assertion that monoallelic (heterozygous) carrier status for MYH variants confers an elevated risk of colorectal cancer was unsupported by available data.
Cheadle and Sampson (2003) reviewed the molecular pathology and biochemistry of MYH colonic polyposis.
Other Associations
Studies by Al-Tassan et al. (2004) appeared to exonerate the MYH gene as a predisposing factor in lung cancer.
Increased oxygen free radicals produced in gastric mucosa by H. pylori (see 600263) induce DNA damage and lead to dysplasia and gastric cancers (137215); however, only a small percentage of individuals who carry H. pylori develop gastric cancer, indicating that other factors are involved. Kim et al. (2004) screened a set of 95 sporadic gastric cancers for mutations and allele loss of the DNA glycosylase MYH gene, which excises adenine misincorporated opposite unrepaired 8-oxoG. Two of 95 cancers had biallelic mutations of the MYH gene with somatic missense mutation of 1 allele and loss of the remaining allele. The mutations, pro391 to ser (P391S; 604933.0006) and gln400 to arg (Q400R; 604933.0007), occurred in exon 13, which encodes the NUDIX (nucleoside diphosphate linked to some other moiety X) hydrolase domain (codons 366-497) of the gene. The patients were H. pylori-positive and the tumors were of advanced intestinal-type gastric cancer with lymph node metastasis. In addition, 4 (17.4%) of 23 informative cases showed allele loss at the MYH locus. Kim et al. (2004) concluded that somatic mutations of the base excision repair gene MYH contribute to the development of a subset of sporadic gastric cancers.
In a Welsh family in which 3 sibs had familial adenomatous polyposis-2 (FAP2; 608456), Al-Tassan et al. (2002) could find no clear germline pathogenic change in the APC gene. However, they showed that 11 tumors from the 3 affected sibs contained 18 somatic inactivating mutations of APC and that 15 of these mutations were G:C-T:A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the mutY gene showed that the affected sibs were compound heterozygous for 2 missense variants, tyr165 to cys (Y165C) and gly382 to asp (G382D; 604933.0002). Thus, defective base excision repair was implicated by these findings in predisposition to tumors in humans.
Sieber et al. (2003) found the germline Y165C mutation in homozygous or compound heterozygous state in 5 of 12 patients from the UK with multiple adenomas.
Barnetson et al. (2007) reported a patient with endometrial adenocarcinoma (see 608089) and sebaceous carcinoma of the face who was compound heterozygous for the Y165C and G382D mutations. Colonic adenomas were not reported, but a paternal aunt reportedly had colorectal cancer in her thirties. Barnetson et al. (2007) noted that the phenotype associated with biallelic MUTYH mutations may include extracolonic manifestations, including endometrial cancer and sebaceous carcinoma, as seen in other inherited colorectal cancer syndromes.
For discussion of the gly382-to-asp (G382D) mutation in the MUTYH gene that was found in compound heterozygous state in patients with familial adenomatous polyposis-2 (FAP2; 608456) by Al-Tassan et al. (2002) and in a patient with endometrial adenocarcinoma (see 608089) by Barnetson et al. (2007), see 604933.0001.
Sieber et al. (2003) found the G382D mutation in compound heterozygous or homozygous state in 6 patients in the UK with multiple colorectal adenomas (608456).
In a 45-year-old French man who was found to have 25 colorectal adenomas on colonoscopy, Rouleau et al. (2011) identified compound heterozygosity for G382D and a large rearrangement of the MUTYH gene resulting in the deletion of exons 3 to 16 (604933.0009).
In a female patient in the United Kingdom who was diagnosed with multiple (18) adenomas (608456) at age 57 years and who also had colorectal cancer and a family history of both, Sieber et al. (2003) identified a 1419delC frameshift mutation in codon 473 of the MUTYH gene in compound heterozygous state with a Y165C mutation (604933.0001).
In a Pakistani patient with multiple colorectal adenomas (FAP2; 608456), Jones et al. (2002) identified homozygosity for a 270C-A mutation in exon 3 of the MUTYH gene, resulting in a tyr90-to-ter (Y90X) substitution.
In 3 patients with multiple colorectal adenomas (FAP2; 608456) from unrelated Indian families, Jones et al. (2002) identified homozygosity for a 494A-G mutation in exon 14 of the MUTYH gene, resulting in a glu466-to-ter (E466X) substitution.
In gastric cancer (137215) tissue from a patient who was a carrier of H. pylori (see 600263), Kim et al. (2004) identified a change at codon 391 of the MUTYH gene from CCG (pro) to TCG (ser) (P391S).
In gastric cancer (137215) tissue from a patient who was a carrier of H. pylori (see 600263), Kim et al. (2004) identified a change at codon 400 of the MUTYH gene from CAG (gln) to GGG (arg) (Q400R).
In a brother and sister, the offspring of first-cousin parents, with association of multiple adenomatous polyps of the colon (FAP2; 608456) with childhood pilomatricomas, Baglioni et al. (2005) identified a homozygous 2-bp insertion in exon 13 of the MUTYH gene, 1186insGG, resulting in a frameshift and a premature stop codon at position 438. The brother also had early-onset rectal adenocarcinoma. Baglioni et al. (2005) investigated exon 3 of the CTNNB1 gene (116806), mutations in which have been associated with pilomatricomas (132600), in 3 pilomatricomas from one of the affected sibs. Although no CTNNB1 mutations were found in these samples, it is still possible that other genes acting in the same pathway, such as APC (611731), were involved in pilomatricoma development in these sibs.
For discussion of the rearrangement of the MUTYH gene resulting in the deletion of exons 3 to 16 that was found in a patient with multiple colorectal adenomas (FAP2; 608456) by Rouleau et al. (2011), see 604933.0002.
Al-Tassan, N., Chmiel, N. H., Maynard, J., Fleming, N., Livingston, A. L., Williams, G. T., Hodges, A. K., Davies, D. R., David, S. S., Sampson, J. R., Cheadle, J. P. Inherited variants of MYH associated with somatic G:C-T:A mutations in colorectal tumors. Nature Genet. 30: 227-232, 2002. [PubMed: 11818965] [Full Text: https://doi.org/10.1038/ng828]
Al-Tassan, N., Eisen, T., Maynard, J., Bridle, H., Shah, B., Fleishmann, C., Sampson, J. R., Cheadle, J. P., Houlston, R. S. Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma. Hum. Genet. 114: 207-210, 2004. [PubMed: 14579148] [Full Text: https://doi.org/10.1007/s00439-003-1033-2]
Baglioni, S., Melean, G., Gensini, F., Santucci, M., Scatizzi, M., Papi, L., Genuardi, M. A kindred with MYH-associated polyposis and pilomatricomas. Am. J. Med. Genet. 134A: 212-214, 2005. [PubMed: 15690400] [Full Text: https://doi.org/10.1002/ajmg.a.30585]
Barnetson, R. A., Devlin, L., Miller, J., Farrington, S. M., Slater, S., Drake, A. C., Campbell, H., Dunlop, M. G., Porteous, M. E. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin. Genet. 72: 551-555, 2007. [PubMed: 17956577] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00900.x]
Cheadle, J. P., Sampson, J. R. Exposing the MYtH about base excision repair and human inherited disease. Hum. Molec. Genet. 12: R159-R165, 2003. [PubMed: 12915454] [Full Text: https://doi.org/10.1093/hmg/ddg259]
Farrington, S. M., Tenesa, A., Barnetson, R., Wiltshire, A., Prendergast, J., Porteous, M., Campbell, H., Dunlop, M. G. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am. J. Hum. Genet. 77: 112-119, 2005. [PubMed: 15931596] [Full Text: https://doi.org/10.1086/431213]
Fromme, J. C., Banerjee, A., Huang, S. J., Verdine, G. L. Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature 427: 652-656, 2004. [PubMed: 14961129] [Full Text: https://doi.org/10.1038/nature02306]
Fry, R. C., Svensson, J. P., Valiathan, C., Wang, E., Hogan, B. J., Bhattacharya, S., Bugni, J. M., Whittaker, C. A., Samson, L. D. Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev. 22: 2621-2626, 2008. [PubMed: 18805990] [Full Text: https://doi.org/10.1101/gad.1688508]
Jones, S., Emmerson, P., Maynard, J., Best, J. M., Jordan, S., Williams, G. T., Sampson, J. R., Cheadle, J. P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-to-T:A mutations. Hum. Molec. Genet. 11: 2961-2967, 2002. [PubMed: 12393807] [Full Text: https://doi.org/10.1093/hmg/11.23.2961]
Kim, C. J., Cho, Y. G., Park, C. H., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., Park, W. S. Genetic alterations of the MYH gene in gastric cancer. Oncogene 23: 6820-6822, 2004. [PubMed: 15273732] [Full Text: https://doi.org/10.1038/sj.onc.1207574]
Lu, A.-L., Fawcett, W. P. Characterization of the recombinant MutY homolog, an adenine DNA glycosylase, from the yeast Schizosaccharomyces pombe. J. Biol. Chem. 273: 25098-25105, 1998. [PubMed: 9737967] [Full Text: https://doi.org/10.1074/jbc.273.39.25098]
Marra, G., Jiricny, J. Multiple colorectal adenomas--is their number up? (Editorial) New Eng. J. Med. 348: 845-847, 2003. [PubMed: 12606740] [Full Text: https://doi.org/10.1056/NEJMe030002]
McGoldrick, J. P., Yeh, Y.-C., Solomon, M., Essigmann, J. M., Lu, A.-L. Characterization of a mammalian homolog of the Escherichia coli MutY mismatch repair protein. Molec. Cell. Biol. 15: 989-996, 1995. [PubMed: 7823963] [Full Text: https://doi.org/10.1128/MCB.15.2.989]
Nghiem, Y., Cabrera, M., Cupples, C. G., Miller, J. H. The mutY gene: a mutator locus in Escherichia coli that generates G:C to T:A transversions. Proc. Nat. Acad. Sci. 85: 2709-2713, 1988. [PubMed: 3128795] [Full Text: https://doi.org/10.1073/pnas.85.8.2709]
Rouleau, E., Zattara, H., Lefol, C., Noguchi, T., Briaux, A., Buecher, B., Bourdon, V., Sobol, H., Lidereau, R., Olschwang, S. First large rearrangement in the MUTYH gene and attenuated familial adenomatous polyposis syndrome. (Letter) Clin. Genet. 80: 301-303, 2011. [PubMed: 21815886] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01699.x]
Sampson, J. R., Dolwani, S., Jones, S., Eccles, D., Ellis, A., Evans, D. G., Frayling, I., Jordan, S., Maher, E. R., Mak, T., Maynard, J., Pigatto, F., Shaw, J., Cheadle, J. P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362: 39-41, 2003. [PubMed: 12853198] [Full Text: https://doi.org/10.1016/S0140-6736(03)13805-6]
Sieber, O. M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R. K. S., Bisgaard, M.-L., Orntoft, T. F., Aaltonen, L. A., Hodgson, S. V., Thomas, H. J. W., Tomlinson, I. P. M. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. New Eng. J. Med. 348: 791-799, 2003. [PubMed: 12606733] [Full Text: https://doi.org/10.1056/NEJMoa025283]
Slupska, M. M., Baikalov, C., Luther, W. M., Chiang, J.-H., Wei, Y.-F., Miller, J. H. Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J. Bacteriol. 178: 3885-3892, 1996. [PubMed: 8682794] [Full Text: https://doi.org/10.1128/jb.178.13.3885-3892.1996]
Thomas, D., Scot, A. D., Barbey, R., Padula, M., Boiteux, S. Inactivation of OGG1 increases the incidence of G:C to T:A transversions in Saccharomyces cerevisiae: evidence for endogenous oxidative damage to DNA in eukaryotic cells. Molec. Gen. Genet. 254: 171-178, 1997. [PubMed: 9108279] [Full Text: https://doi.org/10.1007/s004380050405]
Webb, E. L., Rudd, M. F., Houlston, R. S. Colorectal cancer risk in monoallelic carriers of MYH variants. (Letter) Am. J. Hum. Genet. 79: 768-771, 2006. [PubMed: 16960817] [Full Text: https://doi.org/10.1086/507912]