Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population.
Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population.
复制标题
日本人群中人类 DNA 糖基化酶 MUTYH 的九种错义型变体的功能评估。
DOI：
10.1002/humu.22949
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Sugimura H.
中科院分区：
文献类型：
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作者：
Shinmura K;Kato H;Goto M;Yamada H;Tao H;Nakamura S;Sugimura H.
编码DNA糖基化酶的基因MUTYH的双等位种系突变可导致MUTYH相关息肉病（MAP），其特征是多发性结直肠腺瘤和癌。然而，相当数量的mutyhvariant在功能上仍未被表征。在此，我们报告了日本人群中9种错义型MUTYH变异蛋白的功能评估结果。DNA糖基酶活性和抑制8 -羟基鸟嘌呤（一种氧化形式的鸟嘌呤）引起的突变的能力，分别通过DNA裂解活性测定和前向突变测定，对9种2型MUTYH（一种核形式的酶）变体进行了检测。这两种活性在p.N210S型MUTYH 2型变体中都存在严重缺陷，对应于参考MUTYH形式中的p.N238S，在p.R219G型变体中存在部分缺陷，对应于p.R247G，但在其他七个被检测的变体中几乎完全保留。提示p.N238S和p.R247G可能是MAP的致病等位基因。
Biallelic germline mutations ofMUTYH, the gene encoding DNA glycosylase, cause MUTYH‐associated polyposis (MAP), characterized by multiple colorectal adenomas and carcinoma(s). However, a considerable number ofMUTYHvariants 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 andsupFforward 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.