Using advanced whole genome sequencing in combination with other cell and molecular biology techniques, a mutation in the RAD51 gene was found in an affected child, but not in his parents or his healthy sister. The particular mutation observed in this patient is surprising for two reasons. First, it affects only one of the two RAD51 gene copies in the patient, suggesting a novel origin for the mutation in this patient. More typically, mutations that lead to Fanconi Anemia are derived from both parents (and thus show recessive inheritance). Second, even though only one of the two copies of the patient’s RAD51 gene is affected, the protein product that carries the mutation interferes with the activity of the normal protein which is to repair damage to DNA. Thus the mutation is dominant and acts in a negative way, to impede DNA repair.
This finding has implications for genetic counseling of families facing Fanconi Anemia. Furthermore, understanding the mechanism of action of this mutation shows how the RAD51 protein protects the DNA and how disruptions of DNA repair may lead to birth defects, leukemia and solid tumors. Understanding the origins of human cancer will help diagnose it earlier and may help us devise new therapies to prevent or mitigate it.
This work was organized and sponsored by collaborations between the Institute for Systems Biology, Seattle (USA) with the Luxembourg Center for Systems Biomedicine (Luxembourg), the Free University Medical Center in Amsterdam (The Netherlands) with the assistance of several other institutions or universities in Europe and the United States.