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Mutations of the SLX4 gene in Fanconi anemia


Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors1. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia2. Mutations in thirteen distinct Fanconi anemia genes3 have been shown to interfere with the DNA-replication–dependent repair of lesions involving crosslinked DNA at stalled replication forks4. Depletion of SLX4, which interacts with multiple nucleases and has been recently identified as a Holliday junction resolvase5,6,7, results in increased sensitivity of the cells to DNA crosslinking agents. Here we report the identification of biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P.

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Figure 1: Characterization of cell lines from individuals with Fanconi anemia with SLX4 mutations.
Figure 2: SLX4 is defective in two individuals with Fanconi anemia.
Figure 3: Complementation of RA3083 and RA3331 cells with the SLX4 cDNA.
Figure 4: Interaction of mutant forms of SLX4 with its partners and with ubiquitin.

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We are grateful to the affected individuals and their families for their participation in this study. We thank the Harper Lab, Harvard Medical School, Boston, Massachusetts, USA for reagents, E. Foley for advice and J. de Winter for communicating unpublished results. H.H. is supported by the Deutsche Forschungsgemeinschaft SPP1230, the Bundesministerium für Bildung und Forschung network for Bone Marrow failure Syndrome, and FoneFA. A.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and is a Rita Allen Foundation and an Irma T. Hirschl Scholar.

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The study was designed by A.S., Y.K. and F.P.L. Subject recruitment and sample collection was done by A.D.A., F.P.L. and A.S. Characterization with respect to Fanconi anemia subgroups was performed by A.S., F.P.L., H.H. and A.D.A. Mutation analysis and functional studies were performed by A.S., Y.K., F.P.L. and R.D. The manuscript was written by A.S. with help from other authors.

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Correspondence to Agata Smogorzewska.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Tables 1–3 (PDF 2548 kb)

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Kim, Y., Lach, F., Desetty, R. et al. Mutations of the SLX4 gene in Fanconi anemia. Nat Genet 43, 142–146 (2011).

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