MUTYH gene is located on chromosome 1 and encodes a DNA glyc...

created [InstanceEdit:9605475] Orlic-Milacic, Marija, 2018-04-11
dbId 9605476
displayName MUTYH gene is located on chromosome 1 and encodes a DNA glyc...
modified [InstanceEdit:9612696] Orlic-Milacic, Marija, 2018-06-29
schemaClass Summation
text MUTYH gene is located on chromosome 1 and encodes a DNA glycosylase involved in base excision repair (BER). MUTYH (MYH) functions as an adenine DNA glycosylase and removes adenines and 2-hydroxyadenines on the newly synthesized DNA strand mispaired with guanines or 8-oxoguanines. 8-oxogunanines are produced by oxidation of guanines in DNA or by incorporation of 8-oxodGTP from the nucleotide pool into the newly synthesized DNA strand. Germline mutations in MUTYH cause the MUTYH-associated polyposis (MAP), a syndrome that resembles the familial adenomatous polyposis (FAP) syndrome, caused by mutations in the APC tumor suppressor gene. MAP is also known as the familial adenomatous polyposis 2 (FAP2) (OMIM:608456). MAP-affected individuals are predisposed to development of multiple colorectal adenomas and colorectal cancer. MAP is largely inherited in an autosomally recessive manner, with both MUTYH alleles affected. The predisposition of heterozygous MUTYH mutation carriers to MAP has not been completely ruled out (Fleischmann et al. 2004).

MUTYH is most frequently affected by missense mutations in MAP patients, with two major mutations, Y165C and G382D, reported in about 80% of MAP patients of European origin. In Japanese patients, the most frequently reported mutation was Q324H (Yanaru-Fujisawa et al. 2008). Residues Y165C and G382D in the abundant MUTYH isoform MUTYH alpha-3 (MUTYH-3), used in the majority of functional studies, correspond to Y176C and G393D, respectively, in the canonical UniProt isoform (MUTYH alpha-1) and to Y179C and G396, respectively, in the longest NCBI isoform, which is used as a reference isoform in the database InSiGHT (International Society for Gastrointestinal Hereditary Tumours Database). However, both the canonical UniProt and NCBI MUTYH isoforms are expressed at very low levels or not at all (Plotz et al. 2012). In addition to the isoform MUTYH alpha-3, the other two abundant MUTYH isoforms are MUTYH beta-3 and MUTYH gamma-3 (Plotz et al. 2012), which differ from MUTYH alpha-3 in the first exon used. Exons 1-alpha and 1-beta contain sequences that resemble a mitochondrial targeting signal (MTS). It was reported that MUTYH alpha-3 and MUTYH beta-3 predominantly localize to mitochondria, while MUTYH gamma-3 predominantly localizes to the nucleus (Takao et al. 1999). However, a nuclear localization signal is located at the C-terminus of all MUTYH isoforms and other studies suggested that all isoforms can localize to the nucleus and only a small fraction of MUTYH is targeted to the mitochondria (Ohtsubo et al. 2000, Ichinoe et al. 2004). A small number of functional studies of MUTYH mutants uses the MUTYH isoform gama-3 (Goto et al. 2010, Shinmura et al. 2012). Nuclear localization of MUTYH may be affected by a splicing site variant (Tao et al. 2004).

MAP, compared with APC-associated FAP, is characterized by a later age of onset and a smaller number and size of polyps. Germline MUTYH mutations are associated with an increased incidence of duodenal polyps, gastric cancer, melanoma, breast cancer, dental and dermoid cysts, and osteomas. MUTYH mutations are rarely reported in the sporadic colorectal cancer. Tumors that develop in MAP patients are characterized with an excess of G:C -> T:A transversions in tumor suppressor genes, such as APC, and oncogenes, such as KRAS, which is a consequence of MUTYH functional impairment.

A single nucleotide polymorphism (SNP) at the splice donor site was reported to affect translation efficiency of MUTYH transcript, but its relevance for cancer predisposition has not been clarified (Yamaguchi et al. 2002). Catalytic activity of MUTYH and its mutants may be affected by posttranslational modifications (Parker et al. 2003, Kundu et al. 2010). Some MUTYH mutations reported in colorectal cancer do not affect MUTYH catalytic activity but disrupt the interaction of MUTYH with other proteins involved in DNA repair (Tominaga et al. 2004, Turco et al. 2013).

For review, please refer to Chow et al. 2004, Nielsen et al. 2011, Venesio et al. 2012, Mazzei et al. 2013.
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