MutYH associated polyposis (MAP) is an autosomal recessive type of adenomatous polyposis caused by inheriting biallelic inactivation of MutYH genes. Loss of functional MutYH protein will accumulate G:T mismatched DNA resulted from the oxidative damages. While Y165C and G382D are the 2 most prevalent MutYH mutations in Northern Europeans, more than 60 MutYH missense variants were detected from MAP patients, sporadic colorectal cancers or normal populations. In the genetic diagnosis of MAP, these variants are difficult to determine whether disease causing mutations or single nucleotide polymorphisms. To understand the functional consequence of these variants, we made 48 MutYH gene variations by site directed mutagenesis, then, expressed proteins in the MutY disrupted E. coli and accessed the ability to complement the functional deficiency of the E. coli cells by monitoring the spontaneous mutation rate. While majority of variants showed intermediate complementation compared with wild type, we detected some variants severely interfered in this complementation such as W117R, R168H, R168C, R231H and L374P. On the other hand, some variants such as V22M, G25D, D91N, I209V, V232F, A267V G272E, Q324H, L406M, L515M and R520Q retained almost similar function with wild type. Structural prediction of MutYH based on MutY protein structure allowed us to interpret the effect to the protein stability or catalytic activity of MutYH. In silico prediction functional effects caused by single base alteration showed a good correlation with our functional evaluation for MutYH variants in this study. These data must be useful to evaluate the functional consequence of missense MutYH variants detected in the patients suspected to be affected by MAP.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 478.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO