| Literature DB >> 33355142 |
Yasuyoshi Oka1,2, Motoharu Hamada3, Yuka Nakazawa1,2, Hideki Muramatsu3, Yusuke Okuno3, Koichiro Higasa4,5, Mayuko Shimada1,2, Honoka Takeshima1,2,6, Katsuhiro Hanada7, Taichi Hirano8, Toshiro Kawakita8, Hirotoshi Sakaguchi9, Takuya Ichimura10, Shuichi Ozono11, Kotaro Yuge11, Yoriko Watanabe11, Yuko Kotani12,13, Mutsumi Yamane14, Yumiko Kasugai15, Miyako Tanaka16,17, Takayoshi Suganami16,17, Shinichiro Nakada18,19, Norisato Mitsutake20, Yuichiro Hara1,2, Kohji Kato1,2, Seiji Mizuno21, Noriko Miyake22, Yosuke Kawai23,24, Katsushi Tokunaga23, Masao Nagasaki24,25, Seiji Kito14, Keiichi Isoyama26, Masafumi Onodera27, Hideo Kaneko28, Naomichi Matsumoto22, Fumihiko Matsuda5, Keitaro Matsuo15,29, Yoshiyuki Takahashi3, Tomoji Mashimo12,13,30, Seiji Kojima3, Tomoo Ogi31,2.
Abstract
Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) 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 (ADH5FDH ), 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, Adh5-/-Aldh2 E506K/E506K 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.Entities:
Year: 2020 PMID： 33355142 DOI： 10.1126/sciadv.abd7197
Source DB: PubMed Journal: Sci Adv ISSN： 2375-2548 Impact factor: 14.136