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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 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.

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Figure 1: Genetic analysis of the family carrying an FA-like disorder.
Figure 2: Functional analysis of the RAD51C alleles.
Figure 3: Camptothecin (CPT) sensitivity of lymphoblasts from subject IV-5.

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Acknowledgements

We thank affected individuals and their families for providing samples for this study and for donations to FA research. DNA from matched Pakistani controls was kindly provided by D.A. Khan (Department of Pathology, Army Medical College, Rawalpindi, Pakistan). We thank B. Xia (Department of Radiation Oncology, The Cancer Institute of New Jersey) for providing the PALB2 antibody, A. Sobeck for initial cloning of RAD51C cDNA and R. Kalb and E. Velleuer for constructing an early version of the RAD51C vector and for preliminary analysis. The Rad51c-deficient hamster irs3 cells were a kind gift from J. Thacker (Medical Research Council UK Radiation and Genome Stability Unit), provided by G. Illiakis (Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School). We thank E. Manners for editorial assistance. We are indebted to R. Friedl for flow cytometry and to B. Gottwald and W. Kuss for expert technical assistance. Research in our laboratories was supported by the Medical Research Council UK and the Daniel Ayling Trust (F.V.), the Forschungskommission of the Heinrich Heine University, Düsseldorf (M.F., H.H.), the Deutsche Forschungsgemeinschaft SPP1230 (H.H.), the Bundesministerium für Bildung und Forschung network for congenital bone marrow failure syndromes (H.H., H.S., D.S.), the Deutsche Fanconi Anaemie Hilfe, the Aktionskreis Fanconi Anaemie and the Schroeder Kurth Fund (D.S., H.H.), the Jürgen-Manchot-Stiftung (L.H., H.S.), Cancer Research UK (K.B., N.R.) and European Molecular Biology Organization fellowship ASTF 177-2008 (F.A.).

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Contributions

The study was designed by C.G.M., D.S. and H.H. Phenotypic assessment, sample collection and characterization of FA subgroups were performed by S.M., H.H., D.S., F.V., C.G.M., I.K., C.W., B.S., V.E., K.N. and D.E. Genetic mapping, mutation analysis and functional studies were carried out by F.V., K.B., C.W., B.S., V.E., K.N., D.E., M.F. and L.H. under the supervision of H.H., H.S., D.G., D.S., N.R. and C.G.M. Bioinformatic and structural studies were done by R.G.R., F.A. and F.F. The manuscript was written by C.G.M., D.S. and H.H., with help from the other authors.

Corresponding authors

Correspondence to Helmut Hanenberg, Detlev Schindler or Christopher G Mathew.

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The authors declare no competing financial interests.

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Vaz, F., Hanenberg, H., Schuster, B. et al. Mutation of the RAD51C gene in a Fanconi anemia–like disorder. Nat Genet 42, 406–409 (2010). https://doi.org/10.1038/ng.570

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