Alternative titles; symbols
HGNC Approved Gene Symbol: FANCB
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38) : X:14,689,524-14,873,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.2 | Fanconi anemia, complementation group B | 300514 | X-linked recessive | 3 |
Meetei et al. (2003) purified a Fanconi anemia core complex containing 5 known Fanconi anemia proteins and 4 unknown components called Fanconi anemia-associated polypeptides (FAAPs). By mass spectrometric analysis, Meetei et al. (2004) identified FAAP95 as FLJ34064. FAAP95 has sequence homologs in mouse and chicken, but not in Drosophila melanogaster or Caenorhabditis elegans. The C terminus of the protein contains a putative bipartite nuclear localization signal. FAAP95 was retained mostly in the cytosolic extract of a FANCA (607139)-deficient cell line but became localized to the nuclear extract upon complementation by wildtype FANCA, similar to FANCL (608111).
Meetei et al. (2004) determined that the FAAP95 gene has 10 exons, with the translation start site in exon 3.
By reciprocal immunoprecipitation with FAAP95 antibody, Meetei et al. (2004) demonstrated coprecipitation of several components of the Fanconi anemia core complex, including FANCL, FANCA, and FANCG (602956). FAAP95 coimmunoprecipitated much more FANCL than FANCA or FANCG, suggesting that the interaction between FAAP95 and FANCL may be direct. Meetei et al. (2004) demonstrated that depletion of FAAP95 reduced the amount of monoubiquitinated FANCD2 (227646), similar to depletion of other components of the Fanconi anemia core complex, indicating that FAAP95 protein is a functional component of this complex. Additionally, cells depleted of FAAP95 had less FANCL, suggesting that FAAP95 is required for the stability of FANCL.
The FAAP95 gene is situated in a region of the X chromosome where approximately 60% of the genes escape inactivation and are expressed biallelically. Studies of the methylation status of the gene by Meetei et al. (2004) showed, however, that this is not the case for FAAP95. Results indicated that FAAP95 is subject to total inactivation by methylation and that inactivation seems to be skewed toward the mutated allele. Because X inactivation takes place early in embryogenesis, selection over many subsequent cell generations may lead to almost complete overgrowth by normal cells. The presence of the FAAP95 gene as a single active copy and essentiality for a functional Fanconi anemia-BRCA (see 600185) pathway make FAAP95 a potentially vulnerable component of the cellular machinery that maintains genomic integrity. Although germline mutations in FAAP95 resulting in FANCB are exceedingly rare, somatic FAAP95 mutations might occur at the average spontaneous mutation rate. The occurrence of such Fanconi anemia-like cells may contribute to oncogenesis.
Cryoelectron Microscopy
Shakeel et al. (2019) reconstituted an active, recombinant Fanconi anemia core complex, and used cryoelectron microscopy and mass spectrometry to determine its structure. The FA core complex comprises 2 central dimers of the FANCB and FA-associated protein of 100 kD (FAAP100; 611301) subunits, flanked by 2 copies of the RING finger subunit FANCL. These 2 heterotrimers act as a scaffold to assemble the remaining 5 subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a nonfunctional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL, and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The 2 FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. Shakeel et al. (2019) suggested that this structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases.
Meetei et al. (2004) determined that the FAAP95 gene is localized on chromosome Xp22.31.
In 4 male individuals with Fanconi anemia (300514), Meetei et al. (2004) found different mutations in the FAAP95 gene (300515.0001-300515.0004). In 2 of the 4 families the mother was a carrier, and in 1 of these 2 a sister of the proband was also a carrier. The 3 female FANCB carriers studied were healthy and showed no Fanconi anemia-like symptoms, and their T cells responded normally to challenge with mitomycin C (MMC) without any sign of mosaicism.
Meetei et al. (2004) suggested that evidence that the BRCA2 gene (600185) underlies complementation group B, as suggested by the work of Howlett et al. (2002), was inconclusive. No complementation of a FANCB cell line by BRCA2 was reported, and no BRCA2 mutation was detected in another FANCB cell line; furthermore, cells with defective or depleted BRCA2 show normal monoubiquitination of FANCD2, unlike FANCB cells, which show defective FANCD2 monoubiquitination.
Holden et al. (2006) studied a family in which 2 male fetuses, related to each other as nephew and maternal uncle, had Fanconi anemia presenting as VACTERL with hydrocephalus (VACTERL-H). A fibroblast culture established from the proband fetus showed an increased number of chromosome breaks within the affected range observed in Fanconi anemia cells on breakage studies with diepoxybutane. X-inactivation studies in the mother and maternal grandmother of the proband fetus showed 100% skewing of X inactivation, a feature consistently found in females heterozygous for FANCB mutations. On screening of the 8 coding exons of FANCB, Holden et al. (2006) identified a G-to-A substitution in intron 7 which changed a highly conserved guanine residue at position +5 within the splice donor site (300515.0005). Sequencing of the mutant cDNA fragment from the proband fetus showed that this causes skipping of exon 7. The resulting frameshift in the FANCB transcript resulted in a stop codon at position 446 of the open reading frame. Sequencing of both obligate carrier females, mother and maternal grandmother, confirmed that they were heterozygous for the mutation.
McCauley et al. (2011) found that 4 of 10 probands with Fanconi anemia presenting with a VACTERL-H phenotype had mutations in the FANCB gene (see, e.g., 300515.0006 and 300515.0007). All patients were male, and all unaffected mothers had skewed X inactivation in peripheral blood. Two of the affected pregnancies were terminated at 20 weeks' gestation, 1 proband died at age 15 weeks, and 1 died at age 2 years, 10 months. All patients had multiple severe congenital anomalies, but only the patient who lived beyond the neonatal period developed anemia.
In a Fanconi anemia cell line of complementation group B (300514) (HSC230), Meetei et al. (2004) found a frameshift mutation (1838insT) in exon 8 of the FANCB gene, resulting in a premature stop codon.
In an individual with Fanconi anemia of complementation group B (300514), Meetei et al. (2004) found a 3,314-bp deletion of the FANCB gene that included the promoter region and exon 1 (10693del3314). The mother and sister of the proband were carriers.
In an individual considered a candidate for group B Fanconi anemia (300514) on the basis of exclusion from most of the other complementation groups, inability to monoubiquitinate FANCD2, and male gender, Meetei et al. (2004) found a frameshift mutation, 1650delT, in exon 8 of the FANCB gene.
In an individual selected as a candidate for Fanconi anemia complementation group B (300514) on the basis of exclusion from most of the other complementation groups, inability to monoubiquitinate FANCD2, and male gender, Meetei et al. (2004) found a frameshift mutation, 811insT, in exon 3 of the FANCB gene.
Holden et al. (2006) demonstrated a splice site mutation in the FANCB gene in a fetus with Fanconi anemia (300514) who presented with the VACTERL with hydrocephalus phenotype. A G-to-A substitution in intron 7 mutated a highly conserved guanine residue at position +5 within the splice donor site (IVS7DS+5G-A). Sequencing of the mutant cDNA fragment from the affected male fetus showed that this caused skipping of exon 7, and a frameshift in the FANCB transcript with a stop codon at position 446 of the open reading frame. Both the mother and maternal grandmother were heterozygous for the mutation and showed 100% skewing of X inactivation, with the mutant FANCB allele being preferentially inactivated.
In a 20-week-old male fetus with Fanconi anemia (300514) who presented with the VACTERL with hydrocephalus phenotype, McCauley et al. (2011) identified a 2150T-G transversion in the FANCB gene, resulting in a leu717-to-ter (L717X) substitution. This fetus was a member of a family originally reported by Hunter and MacMurray (1987) as having X-linked VACTERL with hydrocephalus, and again by Wang et al. (1993), who noted that the affected individuals had Fanconi anemia. The maternal grandmother of the fetus reported by McCauley et al. (2011) was an obligate carrier and had highly skewed X inactivation in blood.
In a 20-week-old male fetus with Fanconi anemia presenting as VACTERL with hydrocephalus (300514), McCauley et al. (2011) identified a 2-bp deletion (1857delAG) in the FANCB gene, resulting in a frameshift and premature termination. The mother had highly skewed X inactivation in blood. A maternal male cousin of the fetus died a few hours after delivery with similar multiple congenital malformations.
Holden, S. T., Cox, J. J., Kesterton, I., Thomas, N. S., Carr, C., Woods, C. G. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. J. Med. Genet. 43: 750-754, 2006. [PubMed: 16679491] [Full Text: https://doi.org/10.1136/jmg.2006.041673]
Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297: 606-609, 2002. [PubMed: 12065746] [Full Text: https://doi.org/10.1126/science.1073834]
Hunter, A. G. W., MacMurray, B. Malformations of the VATER association plus hydrocephalus in a male infant and his maternal uncle. Proc. Greenwood Genet. Center 6: 146-147, 1987.
McCauley, J., Masand, N., McGowan, R., Rajagopalan, S., Hunter, A., Michaud, J. L., Gibson, K., Robertson, J., Vaz, F., Abbs, S., Holden, S. T. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. Am. J. Med. Genet. 155A: 2370-2380, 2011. [PubMed: 21910217] [Full Text: https://doi.org/10.1002/ajmg.a.33913]
Meetei, A. R., Levitus, M., Xue, Y., Medhurst, A. L., Zwaan, M., Ling, C., Rooimans, M. A., Bier, P., Hoatlin, M., Pals, G., de Winter, J. P., Wang, W., Joenje, H. X-linked inheritance of Fanconi anemia complementation group B. Nature Genet. 36: 1219-1224, 2004. [PubMed: 15502827] [Full Text: https://doi.org/10.1038/ng1458]
Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Molec. Cell. Biol. 23: 3417-3426, 2003. [PubMed: 12724401] [Full Text: https://doi.org/10.1128/MCB.23.10.3417-3426.2003]
Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A. Structure of the Fanconi anaemia monoubiquitin ligase complex. Nature 575: 234-237, 2019. [PubMed: 31666700] [Full Text: https://doi.org/10.1038/s41586-019-1703-4]
Wang, H., Hunter, A. G. W., Clifford, B., McLaughlin, M., Thompson, D. VACTERL with hydrocephalus: spontaneous chromosome breakage and rearrangement in a family showing apparent sex-linked recessive inheritance. Am. J. Med. Genet. 47: 114-117, 1993. [PubMed: 8368240] [Full Text: https://doi.org/10.1002/ajmg.1320470124]