title: Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.
abstract: Fanconi anemia (FA) is a severe hereditary disorder with defective DNA damage response and repair. It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. Recent studies in mice have suggested that the FA proteins might counteract aldehyde-induced genotoxicity in hematopoietic stem cells. Nearly half of the Japanese population carries a dominant-negative allele (rs671) of the aldehyde-catalyzing enzyme ALDH2 (acetaldehyde dehydrogenase 2), providing an opportunity to test this hypothesis in humans. We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected. Moreover, malformations at some specific anatomic locations were observed more frequently in ALDH2-deficient patients. Our current data indicate that the level of ALDH2 activity impacts pathogenesis in FA, suggesting the possibility of a novel therapeutic approach.
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan;
authors.forename: Asuka
authors.initials: A
authors.lastname: Hira
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yabe
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Miharu
authors.initials: M
authors.lastname: Yabe
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001855:Bone Marrow Diseases / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005199:Fanconi Anemia / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007564:Japan
chemical_list: C498471:FANCA protein, human; C497651:FANCC protein, human; C499909:FANCG protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D052241:Fanconi Anemia Complementation Group G Protein; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
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