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

• Mutator phenotype of MUTYH-null mouse embryonic stem cells [2].
• Biallelic germline mutations in MUTYH were identified in 55 of the 329 unselected patients (17%) and in another 9 selected index cases [12].
• MUTYH also possesses a 2-OH-A DNA glycosylase activity for excising 2-OH-A incorporated into the cellular genomes [13].
• MUTYH excises adenine opposite 8-oxoG, and thus suppresses 8-oxoG-induced mutagenesis [13].
• Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer [14].

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

• Therefore, UNG2 and MYH may serve for replication-coupled base excision repair through the direct interaction with PCNA in the replication machinery [23].

Other interactions of MUTYH

• Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations [3].
• Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes (OGG1 and MTH1) [1].
• Human MYH has been shown to interact physically with human proliferating cell nuclear antigen (hPCNA) [24].
• We also observed gene-gene interactions among OGG1 S326C, XRCC1 R194W, and MUTYH H335Q in ever smokers [25].
• Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage [15].

Analytical, diagnostic and therapeutic context of MUTYH

• Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis [3].
• The PCNA- and RPA-binding sites of hMYH are further confirmed by peptide and antibody titration [26].
• Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer [27].
• Multiplex T-ARMS-PCR allows the detection of 6 common MUTYH mutations with use of as few as 3 single tube PCR reactions [28].
• We then conducted a meta-analysis from published data on the association between mutations at MUTYH and colorectal cancer risk [29].

References