ORPHA: 84; DO: 0111090;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q15.1 | Fanconi anemia, complementation group R | 617244 | Autosomal dominant | 3 | RAD51 | 179617 |
A number sign (#) is used with this entry because of evidence that Fanconi anemia of complementation group R (FANCR) is caused by heterozygous mutation in the RAD51 gene (179617) on chromosome 15q15.
For a discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650).
Ameziane et al. (2015) reported a 23-year-old man with an atypical form of Fanconi anemia. He presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, thumb and radial abnormalities, imperforate anus, and an improperly formed testicle. He did not have bone marrow failure or malignancies. Laboratory studies of patient cells showed hypersensitivity to crosslinking agents, resulting in increased chromosomal breakage and accumulation of cells in the late S-G2 phase of the cell cycle. Patient cells showed normal monoubiquitination of FANCD2 (613984), suggesting a defect downstream of the core FA complex. Additional cellular studies indicated a defect in DNA repair.
Wang et al. (2015) reported a 13-year-old girl who was born with right radial aplasia, absent right thumb, and pelvic left kidney. She also had microcephaly, type I Chiari malformation, tethered spinal cord, and unilateral moderate to severe hearing loss. Additional features included absence of several teeth, scoliosis, and mildly delayed early milestones. However, her IQ was above average and she had no learning disabilities at age 13. She did not have bone marrow failure or malignancies. Laboratory studies showed increased sensitivity to cross-linking agents, indicating a defect in interstrand cross-link DNA repair, although her cells were not sensitive to ionizing radiation, suggesting that the homologous recombination pathway was intact.
The heterozygous mutations in the RAD51 gene that were identified in patients with FANCR by Ameziane et al. (2015) and Wang et al. (2015) occurred de novo.
In a patient with FANCR, Ameziane et al. (2015) identified a de novo heterozygous missense mutation in the RAD51 gene (A293T; 179617.0005). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. In vitro functional expression assays showed that the mutant protein reduced the formation of D-loop intermediates, which measures homology-dependent joint molecule formation during DNA repair by homologous recombination. Biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA and attenuates the DNA-stimulated ATPase activity of RAD51. The mutant protein was unable to form proper and functional nucleoprotein filaments, and acted in a dominant-negative manner when coexpressed with the wildtype protein.
In a girl with FANCR, Wang et al. (2015) identified a de novo heterozygous missense mutation in the RAD51 gene (T131P; 179617.0007). The mutation was found by whole-exome sequencing.
Ameziane, N., May, P., Haitjema, A., van de Vrugt, H. J., van Rossum-Fikket, S. E., Ristc, D., Williams, G. J., Balk, J., Rockx, D., Li, H., Rooimans, M. A., Oostra, A. B., and 17 others. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nature Commun. 6: 8829, 2015. Note: Electronic Article. [PubMed: 26681308] [Full Text: https://doi.org/10.1038/ncomms9829]
Wang, A. T., Kim, T., Wagner, J. E., Conti, B. A., Lach, F. P., Huang, A. L., Molina, H., Sanborn, E. M., Zierhut, H., Cornes, B. K., Abhyankar, A., Sougnez, C., Gabriel, S. B., Auerbach, A. D., Kowalczykowski, S. C., Smogorzewska, A. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Molec. Cell 59: 478-490, 2015. [PubMed: 26253028] [Full Text: https://doi.org/10.1016/j.molcel.2015.07.009]