ORPHA: 84; DO: 0111080;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | ?Fanconi anemia, complementation group V | 617243 | Autosomal recessive | 3 | MAD2L2 | 604094 |
A number sign (#) is used with this entry because of evidence that Fanconi anemia of complementation group V (FANCV) is caused by homozygous mutation in the REV7 gene (MAD2L2; 604094) on chromosome 1p36. One such patient has been reported.
For discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650).
Bluteau et al. (2016) reported an 8-year-old girl, born of distantly related parents, with features consistent with Fanconi anemia. She presented with severe bone marrow failure involving all 3 lineages, short stature, microcephaly, and nonspecific abnormal facial features. She also had a renal tubulopathy and increased serum alpha-fetoprotein. Laboratory studies showed increased chromosomal breakage in response to mitomycin C (MMC), and cellular hypersensitivity to interstrand-crosslinking agents, resulting in increased chromosomal radials, arrest at the G2 phase of the cell cycle, and cell growth inhibition.
The transmission pattern of FANCV in the family reported by Bluteau et al. (2016) was consistent with autosomal recessive inheritance.
In a girl (patient EGF123) with FANCV, Bluteau et al. (2016) identified a homozygous missense mutation in the MAD2L2 gene (V85E; 604094.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed absence of the REV7 protein despite normal transcript levels, suggesting that the mutation results in destabilization of the protein. Expression of wildtype REV7 rescued the chromosomal breakage, cell cycle arrest, and cell proliferation defects observed in patient cells. Knockdown of the REV7 gene in cultured cells resulted in increased chromosome breaks and cellular sensitivity to MMC, as well as G2/M cell cycle arrest. Knockdown of the Rev7 gene in murine hematopoietic cells impaired their ability to form CFU in vitro, consistent with a DNA damage-mediated mechanism of bone marrow failure.
Bluteau, D., Masliah-Planchon, J., Clairmont, C., Rousseau, A., Ceccaldi, R., Dubois d'Enghien, C., Bluteau, O., Cuccuini, W., Gachet, S., Peffault de Latour, R., Leblanc, T., Socie, G., Baruchel, A., Stoppa-Lyonnet, D., D'Andrea, A. D., Soulier, J. Biallelic inactivation of REV7 is associated with Fanconi anemia. J. Clin. Invest. 126: 3580-3584, 2016. Note: Erratum: J. Clin. Invest. 127: 1117 only, 2017. [PubMed: 27500492] [Full Text: https://doi.org/10.1172/JCI88010]