Mutation of the RAD51C gene in a Fanconi anemia–like disorder

Abstract

Christopher Mathew and colleagues report a homozygous germline mutation of RAD51C in a Fanconi anemia-like disorder. Mutation of RAD51C, encoding a protein involved in homologous recombination-mediated DNA repair, leads to hypersensitivity to DNA cross-linking agents. Fanconi anemia (FA) is a rare chromosomal-instability disorder associated with a variety of developmental abnormalities, bone marrow failure and predisposition to leukemia and other cancers1. We have identified a homozygous missense mutation in the RAD51C gene in a consanguineous family with multiple severe congenital abnormalities characteristic of FA. RAD51C is a member of the RAD51-like gene family involved in homologous recombination–mediated DNA repair. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the topoisomerase-1 inhibitor camptothecin. Thus, biallelic germline mutations in a RAD51 paralog are associated with an FA-like syndrome.