Fanconi Anemia, Complementation Group R
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. One such patient has been reported.
For a discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650).
Clinical FeaturesAmeziane 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.
Molecular GeneticsIn 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.