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

Abstract

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 cancers. 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.

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

“…However, no hematological abnormalities or cancers were diagnosed in the children. Sequencing results confirmed the homozygous missense mutation (G773A, R258H) in RAD51C exon 5, and RAD51C has been assigned as FANCO, a 14th in the FA family genes (18,38). In a parallel study, monoallelic mutations in RAD51C were identified to cause breast and ovarian cancers.…”

“…In a striking observation, germ line mutations in RAD51C have been identified to cause FA-like disorder and breast and ovarian cancers (38,39). Biallelic mutation in RAD51C was identified in a family with a characteristic phenotype of FA.…”

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

“…RAD51C maintains genome integrity by participating in branch migration and Holliday junction resolution (12,13,27). Germline mutations in RAD51C confer an increased risk of breast and ovarian cancer (28)(29)(30). According to the previous studies, the role of RAD51C in homologous recombination activation via the regulation of RAD51 recruitment was understood.…”

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

“…Numerous other physiological and cellular abnormalities likely contribute to pathogenesis (Figure 1). The current decade has been prolific for the discovery of novel FA genes Thus, seventeen genes are associated to FA, including the recently discovered genes FANCO/RAD51C [1], FANCP/SLX4 [2,3], FANCQ/ERCC4 [4], and FANCS/BRCA1 [5]. However, following the stringent criteria of at least 2 patients with BMF and a positive chromosome fragility test, only 14 met the criteria for bona fide…”