Defective MUTYH substrate processing

Defective MUTYH substrate processing MUTYH disease variants underlying the MUTYH-associated polyposis (MAP), also known as familial adenomatous polyposis 2 (FAP2), show impaired catalytic activity with respect to cleaving adenine mispaired with 8-oxoguanine (OGUA:Ade, also known as 8-oxoG:A). For some of the mutants, defective substrate processing is further aggravated by reduced substrate binding. MUTYH alpha-3 isoform (MUTYH-3) mutants and MUTYH gamma-3 isoform (MUTYH-6) mutants with experimentally demonstrated deficiency in catalytic activity include missense mutants MUTYH-3 Y165C (MUTYH-6 Y151C), MUTYH-3 R171W, MUTYH-3 R227W, MUTYH-3 R231H, MUTYH-3 R231L, MUTYH-3 V232F, MUTYH-3 R260Q, MUTYH-3 G272E, MUTYH-3 P281L, MUTYH-3 P391L (MUTYH-6 P377L), MUTYH-3 Q324H, MUTYH-3 Q324R,, MUTYH-3 A359V, MUTYH-3 G382D (MUTYH-6 G368D), MUTYH-3 A459D, MUTYH-6 R154H, MUTYH-6 I195V, MUTYH-6 M255V and MUTYH-3 L360P, in-frame indel mutants MUTYH-3 W138_M139insIW (also known as MUTYH 137insIW) and MUTYH-3 E466del (MUTYH-6 E452del), nonsense mutants MUTYH-3 Y90*, MUTYH-3 Q377*, and MUTYH-3 E466*, and frameshift mutant MUTYH-3 A368fs26* (commonly known as MUTYH 1103delC) (Jones et al. 2002, Chmiel et al. 2003, Wooden et al. 2004, Parker et al. 2005, Bai et al. 2005, Alhopuro et al. 2005, Bai et al. 2007, Ali et al. 2008, Yanaru-Fujisawa et al. 2008, Kundu et al. 2009, Forsbring et al. 2009, Molatore et al. 2010, D'Agostino et al. 2010, Goto et al. 2010, Raetz et al. 2012, Shinmura et al. 2012).