Defective MUTYH mutants do not bind adenine mispaired with 8-oxoguanine

Stable Identifier
Reaction [transition]
Homo sapiens
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MUTYH alpha-3 isoform (MUTYH-3) mutants MUTYH-3 Y165C and MUTYH-3 G382D show reduced binding to adenine mispaired with 8-oxoguanine (OGUA:Ade, also known as 8-oxoG:A) (Chmiel et al. 2003, Parker et al. 2005, Ali et al. 2008, Molatore et al. 2010, D'Agostino et al. 2010). MUTYH-3 Y165C and MUTYH-3 G382D are the two most common MUTYH mutations in patients of European origin affected by MUTYH-associated polyposis (MAP), also known as familial adenomatous polyposis 2 (FAP2) (Sieber et al. 2003, Sampson et al. 2003).

MUTYH mutant MUTYH-3 R227W is unable to bind the OGUA:Ade substrate, while the MUTYH-3 V232F mutant shows severely reduced binding. Mutation R231L lies in the same region and MUTYH-3 R231L mutants also show impaired binding to OGUA:Ade. MUTYH-3 R231H mutant, defective in DNA binding, was reported in both adenomatous polyposis (Ali et al. 2008) and lung squamous cell carcinoma.

Mutants MUTYH-3 R260Q and MUTYH-3 P281L show impaired DNA binding, with MUTYH-3 P281L being more severely affected (Ali et al. 2008). In addition to adenomatous polyposis, MUTYH-3 R260Q was reported in stomach cancer and primary sclerosing cholangitis, a risk factor for development of cholangiocarcinoma (Forsbring et al. 2009).

Frameshift mutations in MUTYH, which result in MUTYH protein truncation, also occur in MAP patients. The nonsense mutants MUTYH-3 Y90*, MUTYH-3 Q377* and MUTYH-3 E466*, and frameshift MUTYH-3 A368fs26* (commonly known as MUTYH 1103delC) are not able to bind target DNA (Ali et al. 2008).
Literature References
PubMed ID Title Journal Year
20418187 Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis

Albertini, AM, Bossa, C, Mazzei, F, Ranzani, GN, D'Agostino, VG, Torreri, P, Marinoni, I, Minoprio, A, Bignami, M, Petrucci, TC

DNA Repair (Amst.) 2010
15987719 Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair

Tomlinson, IP, Shi, C, Parker, AR, Eshleman, JR, Sieber, OM, Takao, M, Hua, L

Carcinogenesis 2005
12853198 Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH

Sampson, JR, Mak, T, Cheadle, JP, Maynard, J, Dolwani, S, Eccles, D, Frayling, I, Shaw, J, Jones, S, Pigatto, F, Ellis, A, Maher, ER, Evans, DG, Jordan, S

Lancet 2003
18534194 Characterization of mutant MUTYH proteins associated with familial colorectal cancer

Ali, M, Bristow, R, Gallinger, S, Cleary, S, Kim, H, Cupples, C

Gastroenterology 2008
12628248 Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes

Chmiel, NH, David, SS, Livingston, AL

J. Mol. Biol. 2003
19953527 MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay

Degan, P, Barone, F, Albertini, AM, Mazzei, F, Molatore, S, D'Agostino, VG, Russo, MT, Ranzani, GN, Minoprio, A, Matsumoto, Y, Bignami, M

Hum. Mutat. 2010
12606733 Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH

Aaltonen, LA, Bisgaard, ML, Phillips, RK, Thomas, HJ, Lipton, L, Heinimann, K, Tomlinson, IP, Crabtree, M, Orntoft, TF, Fidalgo, P, Sieber, OM, Hodgson, SV

N. Engl. J. Med. 2003
19443904 Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

Forsbring, M, Boberg, KM, Bergquist, A, Schrumpf, E, Karlsen, TH, Dalhus, B, Vik, ES, Bjørås, M, Alseth, I

Carcinogenesis 2009
Normal reaction
Functional status

Loss of function of MUTYH binding LOF mutants [nucleoplasm]

Name Identifier Synonyms
familial adenomatous polyposis DOID:0050424 adenomatous polyposis of the colon
colorectal cancer DOID:9256
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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