title: Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population.
abstract: Biallelic germline mutations of MUTYH, the gene encoding DNA glycosylase, cause MUTYH-associated polyposis (MAP), characterized by multiple colorectal adenomas and carcinoma(s). However, a considerable number of MUTYH variants are still functionally uncharacterized. Herein, we report the results of functional evaluation of nine missense-type MUTYH variant proteins in the Japanese population. The DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, were examined for the nine variants of type 2 MUTYH, a nuclear form of the enzyme, by DNA cleavage activity assay and supF forward mutation assay, respectively. Both activities were severely defective in the p.N210S MUTYH type 2 variant corresponding to p.N238S in the reference MUTYH form and partially defective in p.R219G variant corresponding to p.R247G, but nearly fully retained in seven other variants examined. Our results suggest that p.N238S and p.R247G are likely to be pathogenic alleles for MAP.
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hisami
authors.initials: H
authors.lastname: Kato
authors.affiliation: Division of Carcinogenesis and Prevention, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hong
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D002460:Cell Line; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D056726:Genetic Association Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007564:Japan; D020125:Mutation, Missense
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
keywords: 8-hydroxyguanine; DNA glycosylase; MAP; MUTYH; MUTYH-associated polyposis