Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC

Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control.