ORPHA: 84; DO: 0111085;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q36.1 | ?Fanconi anemia, complementation group U | 617247 | Autosomal recessive | 3 | XRCC2 | 600375 |
A number sign (#) is used with this entry because of evidence that Fanconi anemia of complementation group U (FANCU) is caused by homozygous mutation in the XRCC2 gene (600375) on chromosome 7q36. One such patient has been reported.
For additional general a discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650).
Shamseldin et al. (2012) reported a 2.5-year-old boy, born of consanguineous Saudi Arabian parents, with an atypical form of Fanconi anemia. At birth, he showed microcephaly, left facial nerve palsy, and bilaterally absent thumbs. Further investigation showed ectopic left kidney and patent ductus arteriosus, and radiographs showed complete absence bilaterally of the first metacarpal and scaphoid bones, absent left radius, and hypoplastic right radius. Growth was continuously poor. Chromosome testing in patient fibroblasts showed a marked increase in the frequency of dsDNA breaks in response to damage, indicating a defect in homologous recombination repair. Complementation studies were not performed. Shamseldin et al. (2012) noted the phenotypic similarities to Xrcc2-null mice (Deans et al., 2000). Park et al. (2016) reported follow-up of the patient reported by Shamseldin et al. (2012): at age 7, he showed no signs of bone marrow failure.
The transmission pattern of FANCU in the family reported by Shamseldin et al. (2012) was consistent with autosomal recessive inheritance.
In a 2.5-year-old boy, born of consanguineous Saudi Arabian parents, with FANCU, Shamseldin et al. (2012) identified a homozygous truncating mutation in the XRCC2 gene (R215X; 600375.0001). The mutation was found by whole-exome sequencing followed by autozygome filtering. Park et al. (2016) performed detailed studies on cells derived from the patient reported by Shamseldin et al. (2012). The mutant protein was not found by Western blot analysis, indicating that it is unstable. Expression of wildtype XRCC2 corrected all 3 abnormal cellular phenotypes that were apparent in patient cells: cellular sensitivity to DNA interstrand crosslinking agents, chromosome instability, and accumulation of cells at the G2/M stage of the cell cycle. Patient cells showed normal levels of monoubiquitinated FANCD2 (613984), a central step in the FA pathway, and decreased assembly of RAD51 (179617) foci, suggesting that XRCC2 acts downstream of this event. Patient cells showed defective assembly of the components of the BCDX2 complex, particularly RAD51C (602774). Patient cells also showed increased sensitivity to ionizing radiation, consistent with a defect in proteins that act downstream in the FA pathway.
Deans et al. (2000) found that most homozygous Xrcc2-null mice die midgestation. The few mice that survived to later stages showed developmental abnormalities and died at birth. Neonatal lethality, apparently due to respiratory failure, was associated with a high frequency of apoptotic death of postmitotic neurons in the developing brain, leading to abnormal cortical structure. Embryonic cells showed genetic instability, revealed by a high level of chromosomal aberrations, and were sensitive to gamma-rays. The findings demonstrated that homologous recombination has an important role in endogenous damage repair in the developing embryo.
Deans, B., Griffin, C. S., Maconochie, M., Thacker, J. Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J. 19: 6675-6685, 2000. [PubMed: 11118202] [Full Text: https://doi.org/10.1093/emboj/19.24.6675]
Park, J.-Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., Vance, G. H., Alkuraya, F. S., Hanenberg, H., Andreassen, P. R. Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. J. Med. Genet. 53: 672-680, 2016. [PubMed: 27208205] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103847]
Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. J. Med. Genet. 49: 184-186, 2012. [PubMed: 22232082] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100585]