In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 6, No. 51 ( 2020-12-18)
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.
Type of Medium:
Online Resource
ISSN:
2375-2548
DOI:
10.1126/sciadv.abd7197
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2020
detail.hit.zdb_id:
2810933-8
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