MUTYH (mutY DNA glycosylase, earlier mutY Homolog (E. coli)) is a humangene encoding a DNA glycosylase, MUTYH glycosylase, involved in oxidative DNA damage repair. 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 major oxidatively damaged DNA lesion. 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.
The MUTYH gene is located on the short (p) arm of chromosome 1 between positions 34.3 and 32.1, from base pair 45,464,007 to base pair 45,475,152.
Mutations in the MUTYH gene cause an autosomal recessive form of 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. The risk for developing colon cancer, when colon screening has not commenced, is about 43 to 100% (MUTYH-Associated Polyposis, genereviews 2012)
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)
^ abcParker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL (Feb 2001). "Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair". The Journal of Biological Chemistry. 276 (8): 5547–55. doi:10.1074/jbc.M008463200. PMID11092888.
Cheadle JP, Sampson JR (Oct 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. PMID12915454.
Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, Redston M, Cotterchio M, Knight J, Gryfe R, Gallinger S (Nov 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. PMID15523092.
Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS (Apr 2004). "Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer". International Journal of Cancer. Journal International Du Cancer. 109 (4): 554–8. doi:10.1002/ijc.20020. PMID14991577.
Jones S, Emmerson P, Maynard J, Best JM, Jordan S, Williams GT, Sampson JR, Cheadle JP (Nov 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. PMID12393807.
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. PMID15034862.
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 (Nov 2003). "Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway". Cancer Research. 63 (22): 7595–9. PMID14633673.
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 (Jul 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. PMID12853198.
Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP (Feb 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. PMID12606733.
Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN (Jun 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. PMID15188161.
Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN (Jul 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. PMID15236166.
Brand R, Nielsen M, Lynch H, Infante E (2012). "MUTYH-Associated Polyposis.". GeneReviews. PMID23035301.