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Gene Review

MUTYH  -  mutY homolog

Homo sapiens

Synonyms: A/G-specific adenine DNA glycosylase, MYH, MutY homolog, hMYH
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Disease relevance of MUTYH

  • We show that biallelic MUTYH defects impart a 93-fold (95% CI 42-213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort [1].
  • The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells [2].
  • Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression [3].
  • The in vivo activity of MutY or MYH can be measured by complementation in Escherichia coli mutY mutants or fission yeast Schizosaccharomyces pombe MYH knockout cells [4].
  • Clinical care of patients with biallelic MYH mutations should be similar to that of patients with classic or attenuated familial adenomatous polyposis [5].
  • After further requests, her family case history revealed that her brother had had between 10 and 15 adenomas and turned out to carry both MUTYH germ line mutations [6].

High impact information on MUTYH

  • Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors [7].
  • Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans [7].
  • Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp [7].
  • BACKGROUND & AIMS: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer [3].
  • We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene [3].

Chemical compound and disease context of MUTYH

  • We have 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 [8].
  • Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been associated with multiple colorectal adenomas that display somatic G:C-->T:A transversions in APC [9].
  • Mutant mMUTYH with G365D amino acid substitution, corresponding to a G382D germline mutation of human MUTYH found in familial adenomatous polyposis patients, almost completely retained its DNA glycosylase activity excising adenine opposite 8-oxoG; however, it possessed 1.5% of the wild-type activity excising 2-OH-A opposite guanine [10].
  • G : C --> T : A transversions in k-ras were significantly more frequent in MYH polyposis adenomas than in sporadic or familial adenomatous polyposis-associated tumours (P<or=0.002), and all resulted in a glycine-to-cysteine substitution at codon 12 [11].

Biological context of MUTYH


Anatomical context of MUTYH

  • CONCLUSIONS: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa [3].
  • We describe the detection of the authentic hOGG1 and hMYH proteins in mitochondria, as well as nuclei in human cells, and how their intracellular localization is regulated by alternative splicing of each transcript [15].
  • The interaction of hMutSalpha and hMYH is not observed in several mismatch repair-defective cell lines [16].
  • By expressing the epitope-tagged proteins in COS-7 cells, we examined subcellular localizations of gene products of human DNA glycosylases: hOGG1, hMYH and hNTH1 [17].
  • A protein homologous to the Escherichia coli MutY protein, referred to as MYH, has been identified in nuclear extracts of calf thymus and human HeLa cells [18].

Associations of MUTYH with chemical compounds

  • The base excision repair DNA glycosylase MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite guanine or 7,8-dihydro-8-oxo-guanine (8-oxoG), thereby preventing G:C to T:A mutations [19].
  • We have shown a significant increase in 8-oxoG in mitochondrial DNA as well as an elevated expression of MTH1, OGG1, and MUTYH in nigrostriatal dopaminergic neurons of PD patients, suggesting that the buildup of these lesions may cause dopamine neuron loss [20].
  • Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo [21].
  • Finally, we surprisingly find that defective MUTYH may not alter cell survival after hydrogen peroxide and menadione treatments [22].
  • Major substrates of these enzymes, a uracil opposite an adenine for UNG2 and an adenine opposite an 8-oxoguanine for MYH, are formed during DNA replication [23].

Physical interactions of MUTYH


Other interactions of MUTYH


Analytical, diagnostic and therapeutic context of MUTYH


  1. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Farrington, S.M., Tenesa, A., Barnetson, R., Wiltshire, A., Prendergast, J., Porteous, M., Campbell, H., Dunlop, M.G. Am. J. Hum. Genet. (2005) [Pubmed]
  2. Mutator phenotype of MUTYH-null mouse embryonic stem cells. Hirano, S., Tominaga, Y., Ichinoe, A., Ushijima, Y., Tsuchimoto, D., Honda-Ohnishi, Y., Ohtsubo, T., Sakumi, K., Nakabeppu, Y. J. Biol. Chem. (2003) [Pubmed]
  3. Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis. Di Gregorio, C., Frattini, M., Maffei, S., Ponti, G., Losi, L., Pedroni, M., Venesio, T., Bertario, L., Varesco, L., Risio, M., Ponz de Leon, M. Gastroenterology (2006) [Pubmed]
  4. Isolation and analyses of MutY homologs (MYH). Lu-Chang, A.L. Meth. Enzymol. (2006) [Pubmed]
  5. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. Sieber, O.M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R.K., Bisgaard, M.L., Orntoft, T.F., Aaltonen, L.A., Hodgson, S.V., Thomas, H.J., Tomlinson, I.P. N. Engl. J. Med. (2003) [Pubmed]
  6. Identification of patients with (atypical) MUTYH-associated polyposis by KRAS2 c.34G > T prescreening followed by MUTYH hotspot analysis in formalin-fixed paraffin-embedded tissue. van Puijenbroek, M., Nielsen, M., Tops, C.M., Halfwerk, H., Vasen, H.F., Weiss, M.M., van Wezel, T., Hes, F.J., Morreau, H. Clin. Cancer Res. (2008) [Pubmed]
  7. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. 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. Nat. Genet. (2002) [Pubmed]
  8. Genetic alterations of the MYH gene in gastric cancer. 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. Oncogene (2004) [Pubmed]
  9. Role of inherited defects of MYH in the development of sporadic colorectal cancer. Kambara, T., Whitehall, V.L., Spring, K.J., Barker, M.A., Arnold, S., Wynter, C.V., Matsubara, N., Tanaka, N., Young, J.P., Leggett, B.A., Jass, J.R. Genes Chromosomes Cancer (2004) [Pubmed]
  10. A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA. Ushijima, Y., Tominaga, Y., Miura, T., Tsuchimoto, D., Sakumi, K., Nakabeppu, Y. Nucleic Acids Res. (2005) [Pubmed]
  11. Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Jones, S., Lambert, S., Williams, G.T., Best, J.M., Sampson, J.R., Cheadle, J.P. Br. J. Cancer (2004) [Pubmed]
  12. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Aretz, S., Uhlhaas, S., Goergens, H., Siberg, K., Vogel, M., Pagenstecher, C., Mangold, E., Caspari, R., Propping, P., Friedl, W. Int. J. Cancer (2006) [Pubmed]
  13. The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. Nakabeppu, Y., Tsuchimoto, D., Furuichi, M., Sakumi, K. Free Radic. Res. (2004) [Pubmed]
  14. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas. Isidro, G., Laranjeira, F., Pires, A., Leite, J., Regateiro, F., Castro e Sousa, F., Soares, J., Castro, C., Giria, J., Brito, M.J., Medeira, A., Teixeira, R., Morna, H., Gaspar, I., Marinho, C., Jorge, R., Brehm, A., Ramos, J.S., Boavida, M.G. Hum. Mutat. (2004) [Pubmed]
  15. Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Nakabeppu, Y. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  16. Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. Gu, Y., Parker, A., Wilson, T.M., Bai, H., Chang, D.Y., Lu, A.L. J. Biol. Chem. (2002) [Pubmed]
  17. Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Takao, M., Aburatani, H., Kobayashi, K., Yasui, A. Nucleic Acids Res. (1998) [Pubmed]
  18. Characterization of a mammalian homolog of the Escherichia coli MutY mismatch repair protein. McGoldrick, J.P., Yeh, Y.C., Solomon, M., Essigmann, J.M., Lu, A.L. Mol. Cell. Biol. (1995) [Pubmed]
  19. Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis. Bai, H., Jones, S., Guan, X., Wilson, T.M., Sampson, J.R., Cheadle, J.P., Lu, A.L. Nucleic Acids Res. (2005) [Pubmed]
  20. Oxidative damage in nucleic acids and Parkinson's disease. Nakabeppu, Y., Tsuchimoto, D., Yamaguchi, H., Sakumi, K. J. Neurosci. Res. (2007) [Pubmed]
  21. Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo. Yamane, A., Shinmura, K., Sunaga, N., Saitoh, T., Yamaguchi, S., Shinmura, Y., Yoshimura, K., Murakami, H., Nojima, Y., Kohno, T., Yokota, J. Carcinogenesis (2003) [Pubmed]
  22. Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair. Parker, A.R., Sieber, O.M., Shi, C., Hua, L., Takao, M., Tomlinson, I.P., Eshleman, J.R. Carcinogenesis (2005) [Pubmed]
  23. Molecular mechanism of PCNA-dependent base excision repair. Matsumoto, Y. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  24. Functional interaction of MutY homolog with proliferating cell nuclear antigen in fission yeast, Schizosaccharomyces pombe. Chang, D.Y., Lu, A.L. J. Biol. Chem. (2002) [Pubmed]
  25. High-order interactions among genetic variants in DNA base excision repair pathway genes and smoking in bladder cancer susceptibility. Huang, M., Dinney, C.P., Lin, X., Lin, J., Grossman, H.B., Wu, X. Cancer Epidemiol. Biomarkers Prev. (2007) [Pubmed]
  26. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. Parker, A., Gu, Y., Mahoney, W., Lee, S.H., Singh, K.K., Lu, A.L. J. Biol. Chem. (2001) [Pubmed]
  27. Oxidative DNA damage and human cancer: need for cohort studies. Loft, S., Møller, P. Antioxid. Redox Signal. (2006) [Pubmed]
  28. Multiplex tetra-primer amplification refractory mutation system PCR to detect 6 common germline mutations of the MUTYH gene associated with polyposis and colorectal cancer. Piccioli, P., Serra, M., Gismondi, V., Pedemonte, S., Loiacono, F., Lastraioli, S., Bertario, L., De Angioletti, M., Varesco, L., Notaro, R. Clin. Chem. (2006) [Pubmed]
  29. Association of MUTYH and colorectal cancer. Tenesa, A., Campbell, H., Barnetson, R., Porteous, M., Dunlop, M., Farrington, S.M. Br. J. Cancer (2006) [Pubmed]
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