Oxidative stress as a multiple effector in Fanconi anaemia clinical phenotype

A review. Fanconi anemia (FA) is a genetic disease characterised by bone marrow failure with excess risk of myelogenous leukemia and solid tumors. A widely accepted notion in FA research invokes a deficiency of response to DNA damage as the fundamental basis of the 'crosslinker sensitivity' obsd. in this disorder. However, such an isolated defect cannot readily account for the full cellular and clin. phenotype, which includes a no. of other abnormalities, such as malformations, endocrinopathies, and typical skin spots. An extensive body of evidence pointing toward an involvement of oxidative stress in the FA phenotype includes the following: (i) In vitro and ex vivo abnormalities in a no. of redox status endpoints; (ii) the functions of several FA proteins in protecting cells from oxidative stress; (iii) redox-related toxicity mechanisms of the xenobiotics evoking excess toxicity in FA cells. The clin. features in FA and the in vivo abnormalities of redox parameters are here reconsidered in view of the pleiotropic clin. phenotype and known biochem. and mol. links to an in vivo prooxidant state, which causes oxidative damage to biomols., resulting in an excessive no. of acquired abnormalities that may overwhelm the cellular repair capacity rather than a primary deficiency in DNA repair. FA may thus represent a unique model disease in testing the integration between the acquisition of macromol. damage as a result of oxidative stress and the ability of the mammalian cell to respond effectively to such damage.