Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome PMID: 33355142

ADC Targets in Oncology

2026-04-10

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

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. [email protected].

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 (ADH5^FDH ), 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.