Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model

Abstract

[Background] Fanconi anemia (FA) is a devastating hereditary disorder for which we desperately need a novel therapeutic strategy. It is caused by mutations in one of at least 22 genes in the FA pathway and is characterized by developmental abnormalities, bone marrow failure, and cancer predisposition. The FA pathway is required for the efficient repair of damaged DNA, including interstrand cross-links (ICL). Recent studies indicate formaldehyde as an ultimate endogenous cause of DNA damage in FA pathophysiology. Formaldehyde can form DNA adducts as well as ICLs by inducing covalent linkages between opposite strands of double-stranded DNA. [Methods and results] In this study, we generated a disease model of FA in zebrafish by disrupting the ube₂t or fancd₂ gene, which resulted in a striking phenotype of female-to-male sex reversal. Since formaldehyde is detoxified from the body by alcohol dehydrogenase₅ (ADH₅), we generated fancd₂⁻/⁻/adh₅⁻/⁻ zebrafish. We observed a body size reduction and a lower number of mature spermatozoa than wild-type or single knockout zebrafish. To evaluate if increased activity in ADH₅ can affect the FA phenotype, we overexpressed human ADH₅ in fancd₂⁻/⁻zebrafish. The progress of spermatogenesis seemed to be partially recovered due to ADH₅ overexpression. [Conclusions] Our results suggest potential utility of an ADH₅ enzyme activator as a therapeutic measure for the clearance of formaldehyde and treatment of FA.