MUTYH

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External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
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Wikidata
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MUTYH (mutY DNA glycosylase) is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

The protein is localized to the nucleus and mitochondria. Mutations in this gene result in heritable predisposition to colon and stomach cancer. Multiple transcript variants encoding different isoforms have been found for this gene.

Location & Structure

MUTYH has its locus on the short (p) arm of chromosome 1 (1p34.1), from base pair 45,464,007 to base pair 45,475,152 (45,794,835-45,806,142). The gene is composed of 16 exons and has a size of 546 amino acids. and is approximately 7.1kb. The presence of disulfide crosslinking gives rise to a complex crystal structure of the MUTY-DNA. The protein structure of the MUTYH gene has its N- terminal on the 5’ and the C-terminal on the 3’. Within the N-terminal. There is an helix-hairpin-helix and pseudo helix-hairpin-helix contained within the N-terminal, in addition to and iron cluster motif

Mechanism

Repair of oxidative DNA damage is the result of a collaborative effort of MUTYH, OGG1, and MTH1. MUTYH gene acts on the adenine base that have an A to 8-oxoG pairing while OGG1 (on chromosome 3 (3p26.2) part of the base excision repair pathway) detects and acts on 8-oxoG, thereby removing it. The resultant effect of the action of the genes results in correction of transversion mutations made by the incorrect G:C, T:A pairing. TP53 transcriptionally regulates MUTYH and it can be surmised that it may potentially act as a regulator for p53.

Expression

MUTYH is overexpressed in CD4-T cells, the prostate, the colon and the rectum. There is evidence of MUTYH expression in kidney, intestinal, nervous system and muscle tissues.

Protein interactions

MUTYH has been shown to interact with Replication protein A1, PCNA and APEX1.

The excision of the bases causes the formation of an apurinic/ apyrimidinic (AP site) gap. These gap sites are mutagenic in nature and require constant and immediate emendation and this is achieved by the active involvement of protein complexes that repair the AP gap site via short and long patch repair pathways. The short patch repair pathway employs POLB (DNA polymerase beta), APE1, XRCC1, PARP1 with the addition of either the LIG1 or LIG3 genes. When an insertion of one nucleotide occurs, the enzyme AP endonuclease (APEX/APE1) cuts out the mismatched base pairs at the AP site and this causes the evolvement of 5’dRP (5’ deoxyribose phosphate), a terminal blocking group, and 3’-OH ( 3’ hydroxyl end). POLB is required to remove the 5’dRP, and it does this by enzymatic activity, namely polymerase and dRP lyase. DNA ligase is used to seal the fragments after dRP excision causes the formation of 5’PO4 that is necessary to form the phosphodiester bonds of DNA. The purpose of PARP1 and XRCC1 in the single strand break repair pathway, is to stabilize the strands of DNA while they undergo repair, synthesis, gap-filling and ligation. PARP1 acts as a recruit agent for XRCC1. The nick sealing of the strands is accomplished by the formation of LIG1 (DNA ligase 1) and/or LIG3/ XRCCI complex that attach to processed end of the corrected strands and reinstate the original conformation of the strand. Long patch repair comes into play when more nucleotides are involved, ranging from 2 to 12. It is hypothesized that Polymerase 𝜹 (POLD) and Polymerase 𝛆 (POLE), assisted by the PCNA (proliferating cell nuclear antigen) in conjunction with replication factor C (RFC) that acts as a stabilizer and places newly synthesized nucleotides on the DNA strand. Both the polymerases repair the DNA by employing the strand displacement synthesis mechanism. This mechanism occurs downstream a DNA strand and the 5’ is transformed into a “flap intermediate” causing it to be “displaced”. FEN1 ( flap structure-specific endonuclease 1), a nuclease, removes the displaced strand and this results in a ligatable strand of DNA.Long patch repair, like short patch repair, includes the use of APE1 and PARP1 and LIG1. The repair pathway is partially determined by the amount of ATP present after the removal of the deoxyribose phosphate end. The long patch repair pathway is preferred under conditions of low ATP concentration while the short repair pathway is preferred under high concentrations of ATP.

Other notable interactions include MUTYH and Replication protein A is a single strand binding protein that prevents the annealing of DNA during replication, it also plays a role as an activator for damage repair on DNA. There is a hypothetical relation between the interaction of Mismatch Repair proteins (MMR) such as MSH 2,3 and 6, MLH1, PMS1 and 2, and MUTYH in which the proposed result of their partnering is to increase susceptibility to cancer.

Chemical interactions

The gene interacts with the following chemicals:

a) Carbon tetrachloride : decreased expression of MUTYH mRNA

b) Ethanol: When treated together with dronabinol) increased expression of MUTYH mRNA. When used alone, it has conflicting results of decreased and increased the MUTYH mRNA.

c) Ethinylestradiol: When used alone it results in the increased expression of MUTYH mRNA.When treated together with tetrachlorodibenzo p dioxin, there is increased expression of MUTYH mRNA.

d) Tamoxifen: affects MUTYH

Related conditions

The table of the Gene-phenotype associations summarizes the diseases/conditions that arise from mutations in MUTYH

Phenotype/Condition	Mode of Inheritance
Familial adenomatous polyposis	Autosomal recessive
Pilomatricoma	Somatic mutation
Gastric cancer	Somatic mutation

Mutations in the MUTYH gene cause an autosomal recessive disorder similar to familial adenomatous polyposis (also called MUTYH-associated polyposis). Polyps caused by mutated MUTYH do not appear until adulthood and are less numerous than those found in patients with APC gene mutations. Both copies of the MYH gene are mutated in individuals who have autosomal recessive familial adenomatous polyposis i.e., the mutations for the MUTYH gene is biallelic .Mutations in this gene affect the ability of cells to correct mistakes made during DNA replication. Both copies of the MYH gene are mutated in individuals who have autosomal recessive familial adenomatous polyposis. Most reported mutations in this gene cause production of a nonfunctional or low functioning glycosylase enzyme. When base excision repair in the cell is compromised, mutations in other genes build up, leading to cell overgrowth and possibly tumor formation. The two most common mutations in Caucasian Europeans are exchanges of amino acids (the building blocks of proteins) in the enzyme. One mutation replaces the amino acid tyrosine with cysteine at position 179 (also written as p.Tyr179Cys (p.Y179C) or, when describing the nucleotide change, written as c.536A>G) The other common mutation switches the amino acid glycine with aspartic acid at position 396 (also written as p.Gly396Asp(G396D)or c.1187G>A)

The association of the gene with gastric cancer is somewhat indirect and multifactorial. When a subject is infected with Helicobacter pylori (H.pylori), the bacteria cause the formation of free oxygen radicals that are present in the gastric mucosa and this increases the propensity of the genes to incur oxidative damage . A study of 95 cases of patients who had sporadic cancers, initiated by the presence of H.pylori, and two of the 95 patients had biallelic mutation of the MUTYH gene. The somatic missense mutations for the first identified cancer occurred at codon 391, in which there was a change in the nucleotide bases from CCG ( codon for amino acid proline) to TCG ( codon for amino acid serine), while the second cancer had a nucleotide base change at codon 400 from CAG ( codon for amino acid glutamine) to GGG( codon for amino acid arginine). The mutations were found to be highly conserved in the Nudix hydrolase domain of MUTYH. These amino acid mutations provide the basis for the somatic mutations in the gastric system.

Pilomatricoma has been noted in a case that concerned two siblings who were the offspring of consanguineous parents. The siblings had a 2 base pair homozygous insertion on the MUTYH gene ( exon 13). Consequently, a frameshift occurred due to the insertion and a premature stop codon was read at 438 on the gene. Pilomatricoma was the phenotypic manifestation of this mutation. One of the siblings was also found to have rectal adenocarcinoma. It is worthy to note that CTNNB1, a gene associated with pilomatricoma, was also investigated. However, no mutations in this gene were found, thereby dismissing it as a possible cause for this case.

There is an established correlation between aging and the elevation 8-oxoG concentrations, particularly in organs that exhibit reduced cell proliferation such as the kidneys, liver, brain and lungs. Presence of 8-oxoG also occurs in large concentrations in patients with neurological conditions such as Alzheimer’s, Parkinson’s and Huntington’s disease. MUTYH causes immoderate formation of single stranded breaks via base excision repair, under acute oxidative stress conditions. When the 8-oxoguanine species accumulate and increase in concentration in the neurons, MUTYH responds by triggering their degeneration.

Further reading

• Cheadle JP, Sampson JR (October 2003). "Exposing the MYtH about base excision repair and human inherited disease". Human Molecular Genetics. 12 Spec No 2 (90002): R159–65. doi:10.1093/hmg/ddg259. PMID 12915454.
• Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, Redston M, Cotterchio M, Knight J, Gryfe R, Gallinger S (November 2004). "Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk". Journal of the National Cancer Institute. 96 (21): 1631–4. doi:10.1093/jnci/djh288. PMID 15523092.
• Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS (April 2004). "Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer". International Journal of Cancer. 109 (4): 554–8. doi:10.1002/ijc.20020. PMID 14991577.
• Jones S, Emmerson P, Maynard J, Best JM, Jordan S, Williams GT, Sampson JR, Cheadle JP (November 2002). "Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations". Human Molecular Genetics. 11 (23): 2961–7. doi:10.1093/hmg/11.23.2961. PMID 12393807.
• Jones S, Lambert S, Williams GT, Best JM, Sampson JR, Cheadle JP (April 2004). "Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas". British Journal of Cancer. 90 (8): 1591–3. doi:10.1038/sj.bjc.6601747. PMC 2410274. PMID 15083190.
• Kambara T, Whitehall VL, Spring KJ, Barker MA, Arnold S, Wynter CV, Matsubara N, Tanaka N, Young JP, Leggett BA, Jass JR (May 2004). "Role of inherited defects of MYH in the development of sporadic colorectal cancer". Genes, Chromosomes & Cancer. 40 (1): 1–9. doi:10.1002/gcc.20011. PMID 15034862.
• Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML, Hodgson SV, Aaltonen LA, Thomas HJ, Tomlinson IP (November 2003). "Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway". Cancer Research. 63 (22): 7595–9. PMID 14633673.
• Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, Frayling I, Jordan S, Maher ER, Mak T, Maynard J, Pigatto F, Shaw J, Cheadle JP (July 2003). "Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH". Lancet. 362 (9377): 39–41. doi:10.1016/S0140-6736(03)13805-6. PMID 12853198.
• Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP (February 2003). "Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH". The New England Journal of Medicine. 348 (9): 791–9. doi:10.1056/NEJMoa025283. PMID 12606733.
• Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN (June 2004). "High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis". Gastroenterology. 126 (7): 1681–5. doi:10.1053/j.gastro.2004.02.022. PMID 15188161.
• Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN (July 2004). "MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps". Gastroenterology. 127 (1): 9–16. doi:10.1053/j.gastro.2004.03.070. PMID 15236166.
• "MUTYH-Associated Polyposis". GeneReviews. 2012. PMID 23035301.
• Nielsen M, Morreau H, Vasen HF, Hes FJ (July 2011). "MUTYH-associated polyposis (MAP)". Critical Reviews in Oncology/Hematology. 79 (1): 1–16. doi:10.1016/j.critrevonc.2010.05.011. PMID 20663686.

External links

• Online Mendelian Inheritance in Man (OMIM) 604933
• EntrezGene 4595
• GeneCard
• Hereditary Colorectal Cancer Syndromes
• LOVD database [2]