Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

Abstract

Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial-ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA and FancC embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC mice show reduced bone strength compared with their wild-type littermates. Ex vivo cultures showed that FancA and FancC bone marrow-derived mesenchymal stem cells ( MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. © 2018 American Society for Bone and Mineral Research.

Identification of potential pathogenic genes causing occipitalization of the atlas

“…McGaughran et al suggested a relationship between FA and vertebral abnormalities [44]. Mazon et al reported a mouse model with an FA mutant gene that displayed skeletal anomalies such as vertebral fusion and defective bone mineralization [45]. In the present study, 53.6% of patients (15 /28) carried FA-related mutant variants and KEGG analysis indicated that this cohort was affected by FA genetic factors.…”

“…Furthermore, it has been demonstrated that mice with a mutant FA gene are susceptible to the teratogenic effects of ethanol. Such teratogenicity is largely due to acetaldehyde, a by-product of ethanol catabolism [45].…”

A novel RAD51 variant resulting in Fanconi anemia identified in an infant with multiple congenital anomalies

“…Further research on the effect of defective RAD51 on mesenchymal progenitor cell differentiation may reveal downstream effects not yet observed in other FA gene variants. 8 Despite the inability to assess bone marrow failure and malignancy in our patient due to his short survival, the similarities of the other physical findings in all four patients suggests a relatively consistent though expanding phenotype for this rare subgroup of FA. [2][3][4] Since only three prior RAD51-associated cases have been reported to date, it is difficult to discern which characteristics in our patient, such as the respiratory tract anomalies, can be attributed to prematurity verses the underlying condition.…”

“…Experiments involving FA gene knockouts have only assessed the three most common genes in FA ( FANCA , FANCC , and FANCG ). Further research on the effect of defective RAD51 on mesenchymal progenitor cell differentiation may reveal downstream effects not yet observed in other FA gene variants 8 …”

“…Further research on the effect of defective RAD51 on mesenchymal progenitor cell differentiation may reveal downstream effects not yet observed in other FA gene variants. 8 …”