Oka Yasuyoshi, Hamada Motoharu, Nakazawa Yuka, Muramatsu Hideki, Okuno Yusuke, Higasa Koichiro, Shimada Mayuko, Takeshima Honoka, Hanada Katsuhiro, Hirano Taichi, Kawakita Toshiro, Sakaguchi Hirotoshi, Ichimura Takuya, Ozono Shuichi, Yuge Kotaro, Watanabe Yoriko, Kotani Yuko, Yamane Mutsumi, Kasugai Yumiko, Tanaka Miyako, Suganami Takayoshi, Nakada Shinichiro, Mitsutake Norisato, Hara Yuichiro, Kato Kohji, Mizuno Seiji, Miyake Noriko, Kawai Yosuke, Tokunaga Katsushi, Nagasaki Masao, Kito Seiji, Isoyama Keiichi, Onodera Masafumi, Kaneko Hideo, Matsumoto Naomichi, Matsuda Fumihiko, Matsuo Keitaro, Takahashi Yoshiyuki, Mashimo Tomoji, Kojima Seiji, Ogi Tomoo
Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Sci Adv. 2020 Dec 18;6(51). doi: 10.1126/sciadv.abd7197. Print 2020 Dec.
Rs671 in the aldehyde dehydrogenase 2 gene () is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase ( ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.
醛脱氢酶2基因（）中的Rs671是亚洲人饮酒后出现酒精性脸红反应的原因。ALDH2可使内源性醛解毒，内源性醛是通过范可尼贫血途径修复的DNA损伤的主要来源。在此，我们表明，rs671缺陷等位基因与编码甲醛脱氢酶（）的乙醇脱氢酶5基因突变相结合，会导致一种先前未被识别的疾病，即AmeD（再生障碍性贫血、智力发育迟缓及侏儒症）综合征。细胞研究表明，甲醛耐受性降低是造血干细胞分化和增殖能力丧失的基础。此外，双缺陷小鼠重现了AmeDS的关键临床特征，表现出寿命缩短、侏儒症和造血功能衰竭。总体而言，我们的结果表明，甲醛清除机制的联合缺陷会因甲醛诱导的DNA损伤过载而导致复杂的临床特征，从而使DNA修复过程饱和。
