2. Academic Validation
  3. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

  • Sci Adv. 2020 Dec 18;6(51):eabd7197. doi: 10.1126/sciadv.abd7197.
Yasuyoshi Oka 1 2,  Motoharu Hamada 3,  Yuka Nakazawa 1 2,  Hideki Muramatsu 3,  Yusuke Okuno 3,  Koichiro Higasa 4 5,  Mayuko Shimada 1 2,  Honoka Takeshima 1 2 6,  Katsuhiro Hanada 7,  Taichi Hirano 8,  Toshiro Kawakita 8,  Hirotoshi Sakaguchi 9,  Takuya Ichimura 10,  Shuichi Ozono 11,  Kotaro Yuge 11,  Yoriko Watanabe 11,  Yuko Kotani 12 13,  Mutsumi Yamane 14,  Yumiko Kasugai 15,  Miyako Tanaka 16 17,  Takayoshi Suganami 16 17,  Shinichiro Nakada 18 19,  Norisato Mitsutake 20,  Yuichiro Hara 1 2,  Kohji Kato 1 2,  Seiji Mizuno 21,  Noriko Miyake 22,  Yosuke Kawai 23 24,  Katsushi Tokunaga 23,  Masao Nagasaki 24 25,  Seiji Kito 14,  Keiichi Isoyama 26,  Masafumi Onodera 27,  Hideo Kaneko 28,  Naomichi Matsumoto 22,  Fumihiko Matsuda 5,  Keitaro Matsuo 15 29,  Yoshiyuki Takahashi 3,  Tomoji Mashimo 12 13 30,  Seiji Kojima 3,  Tomoo Ogi 31 2
Affiliations

Affiliations

  • 1 Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
  • 2 Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 3 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 4 Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
  • 5 Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 6 School of Medicine, Nagoya University, Nagoya, Japan.
  • 7 Clinical Engineering Research Center, Faculty of Medicine, Oita University, Yufu, Japan.
  • 8 Department of Hematology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.
  • 9 Department of Hematology and Oncology, Children Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
  • 10 Department of Pediatrics, Graduate School of Medicine, Yamaguchi University, Ube, Japan.
  • 11 Department of Pediatrics and Child Health, School of Medicine, Kurume University, Kurume, Japan.
  • 12 Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 13 Genome Editing Research and Development (R&D) Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 14 Center for Animal Research and Education, Nagoya University, Nagoya, Japan.
  • 15 Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • 16 Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
  • 17 Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 18 Department of Bioregulation and Cellular Response, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 19 Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
  • 20 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
  • 21 Department of Pediatrics, Aichi Developmental Disability Center, Kasugai, Japan.
  • 22 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 23 Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 24 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
  • 25 Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
  • 26 Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.
  • 27 Division of Immunology, National Center for Child Health and Development, Tokyo, Japan.
  • 28 Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan.
  • 29 Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 30 Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 31 Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan. togi@riem.nagoya-u.ac.jp.
PMID: 33355142 DOI: 10.1126/sciadv.abd7197
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.

Figures