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Other entities represented in this entry:
HGNC Approved Gene Symbol: BCOR
SNOMEDCT: 699300009;
Cytogenetic location: Xp11.4 Genomic coordinates (GRCh38) : X:40,051,246-40,177,329 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.4 | Microphthalmia, syndromic 2 | 300166 | X-linked dominant | 3 |
The full-length BCOR protein functions as a corepressor for BCL6 (109565), a POZ/zinc finger transcriptional repressor that is required for germinal center formation and may influence apoptosis (Huynh et al., 2000).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned BCOR, which they designated KIAA1575. RT-PCR ELISA detected intermediate BCOR expression in adult liver, kidney, spinal cord, whole brain, and all specific brain regions examined, and in fetal liver. Expression was lower in adult heart, spleen, and ovary, and in fetal brain. Little to no expression was detected in testis, pancreas, lung, and skeletal muscle.
Using a yeast 2-hybrid screen to identify proteins that interact with the POZ domain of BCL6, Huynh et al. (2000) cloned BCOR from a mature B-cell line expression library. The deduced 1,721-amino acid protein contains 3 C-terminal tandem ankyrin repeats. An alternatively spliced variant, which they designated BCOR-S, encodes a deduced 1,004-amino acid protein that is identical to the longer variant up to amino acid 999, after which it has a unique 5-amino acid C terminus. BCOR-S does not contain the ankyrin repeats. Northern blot analysis using a probe unique to the longer BCOR variant detected transcripts of 6.5 and 7.0 kb in HeLa cells and the B-cell line, indicating the presence of a third variant. RNA dot blot analysis detected expression of BCOR in all tissues examined.
Huynh et al. (2000) found that the full-length BCOR protein, but not BCOR-S, functioned as a corepressor when tethered to a promoter DNA element, and when overexpressed it potentiated BCL6 repression. Both BCOR variants associated with specific class I and II histone deacetylases (HDACs), suggesting that BCOR may functionally link these 2 classes of HDACs and that histone/protein deacetylation is a mechanism for BCOR-mediated repression. BCOR interacted selectively with the POZ domain of BCL6, but not with 8 other POZ proteins tested, including PLZF (176797). Interactions between the POZ domain of BCL6 and SMRT (600848), NCOR (600849), and BCOR were mutually exclusive.
Using a bacterial 2-hybrid system, Junco et al. (2013) found that the C-terminal ubiquitin-like fold domains of PCGF1 (610231) and PCGF3 (617543) interacted with the C-terminal domains of BCOR and BCORL1 (300688).
By radiation hybrid analysis, Nagase et al. (2000) mapped the BCOR gene to the X chromosome.
Gross (2017) mapped the BCOR gene to chromosome Xp11.4 based on an alignment of the BCOR sequence (GenBank AF317391) with the genomic sequence (GRCh38).
Pierron et al. (2012) used high-throughput sequencing of cDNAs (RNA-seq) to investigate samples from individuals diagnosed with small round cell tumors of bone that lacked the canonical EWSR1/ETS translocation (133450). A new fusion was observed between BCOR and CCNB3 (300456) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR/CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR/CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Pierron et al. (2012) also showed that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR/CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells.
In affected members of a family originally reported by Hoefnagel et al. (1963) and Ogunye et al. (1975) with syndromic microphthalmia-2 (MCOPS2; 300166), Ng et al. (2004) identified a pro85-to-leu mutation in the BCOR gene (P85L; 300485.0001). Because of phenotypic overlap between the microphthalmia syndrome in this family and oculofaciocardiodental syndrome (OFCD; see 300166), they sequenced BCOR in 10 affected females from 7 OFCD families and found different mutations in each of the 7 families (see 300485.0002-300485.0005), all of which predicted premature stop codons. BCOR with either the P85L mutation or a mutation found in OFCD interacted with BCL6 and efficiently repressed transcription, indicating that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL6.
Horn et al. (2005) identified deletions in the BCOR gene (300485.0006-300485.0008) in 3 unrelated patients with OFCD. However, they did not identify mutations in the BCOR gene in 3 patients with Lenz microphthalmia syndrome (309800) or in 5 patients with a phenotype similar to that disorder. The authors concluded that BCOR is the causative gene for OFCD, but is not the major gene involved in Lenz microphthalmia syndrome.
In 34 female patients from 20 families with syndromic microphthalmia, Hilton et al. (2009) identified heterozygous mutations in the BCOR gene (see, e.g., 300485.0003, and 300485.0010-300485.0012). Three patients from 2 families were found to be mosaic; 1 of these patients was asymptomatic, whereas the other 2 exhibited a classic presentation. In addition, an unrelated boy with syndromic microphthalmia was hemizygous for the P85L mutation.
In 2 affected male individuals from a Japanese family with syndromic clinical anophthalmia, Suzumori et al. (2013) identified hemizygosity for the P85L mutation in the BCOR gene.
Ng et al. (2004) cloned the zebrafish ortholog of BCOR and found that knockdown of the ortholog caused developmental perturbations of the eye, skeleton, and CNS consistent with the human disorders Lenz microphthalmia (309800) and OFCD syndrome, confirming that BCOR is a key transcriptional regulator during early embryogenesis.
In 6 affected males from a family with syndromic microphthalmia-2 (MCOPS2; 300166), Ng et al. (2004) identified a 254C-T transition in the BCOR gene, resulting in a pro85-to-leu (P85L) mutation. The mutation cosegregated with the disease in this family (lod = 2.46).
In a 7-year-old boy with microphthalmia, narrow forehead, simple ears, atrial septal defect, multiple partial finger syndactyly, fifth-finger clinodactyly, radioulnar synostosis, mental retardation, and hypospadias, Hilton et al. (2009) identified the P85L mutation in the BCOR gene.
In 2 Japanese male half-sibs, with syndromic clinical anophthalmia, Suzumori et al. (2013) identified the P85L mutation in the BCOR gene. The mother was a heterozygous carrier of P85L. The first boy died of cardiac defects at 6 months of age; in the second affected individual, underdevelopment of fetal eyes was evident on prenatal ultrasound, and analysis of cultured amniotic cells revealed the P85L mutation. The pregnancy was terminated at 19 weeks. Autopsy was declined, but examination confirmed clinical anophthalmia and showed depressed nasal bridge and simple ears.
In a female from a family with oculofaciocardiodental syndrome (MCOPS2; 300166), Ng et al. (2004) identified a G-to-T transition at position -1 of the splice acceptor site of intron 8 of the BCOR gene, which predicted a premature stop codon.
In 3 affected females from a family with oculofaciocardiodental syndrome (MCOPS2; 300166), Ng et al. (2004) identified a 2926C-T transition in the BCOR gene, resulting in an arg976-to-ter (R976X) mutation.
Hilton et al. (2009) identified this mutation in the mother and daughter reported by McGovern et al. (2006) with oculofaciocardiodental syndrome.
In 2 affected females from a family with oculofaciocardiodental syndrome (MCOPS2; 300166), Ng et al. (2004) identified a 1-bp deletion in the BCOR gene, 3881delA, which predicted a premature stop codon.
In an affected female from a family with oculofaciocardiodental syndrome (MCOPS2; 300166), Ng et al. (2004) identified a large deletion encompassing at least exons 9-15 of the BCOR gene, but not involving any other genes.
In a patient with oculofaciocardiodental syndrome (MCOPS2; 300166), Horn et al. (2005) identified a 2-bp deletion (2488_2489delAG) in exon 2 of the BCOR gene. The patient's mother did not carry the mutation, and the father was not available for testing. The deletion was not seen in 100 control X chromosomes.
In a patient with oculofaciocardiodental syndrome (MCOPS2; 300166), Horn et al. (2005) identified a 1-bp deletion (3286delG) in exon 7 of the BCOR gene. The parents were not available for testing, and the deletion was not identified in 100 control X chromosomes.
In a patient with oculofaciocardiodental syndrome (MCOPS2; 300166), Horn et al. (2005) identified a partial, approximately 60-kb deletion in the paternally derived BCOR gene encompassing at least exons 2 to 15. The deletion was a de novo event.
In a patient with oculofaciocardiodental syndrome (MCOPS2; 300166), Oberoi et al. (2005) described a 1-bp deletion (2613delC) in exon 4 of the BCOR gene, predicted to result in a frameshift with a premature protein termination (Phe871Leufs8Ter). (In the article by Oberoi et al. (2005), this deletion is referred to as 2613delC in the abstract, discussion, and figure 4, but as 1315delC in the results.)
In twin sisters and the daughter of 1 of the twins, all with syndromic microphthalmia-2 (MCOPS2; 300166), Hilton et al. (2009) identified a large deletion in the BCOR gene, encompassing at least exons 4 through 15. The 27-year-old monozygotic twin sisters, who both presented a classic phenotype, were found to be somatic mosaic for the deletion; the deletion was non-mosaic in the 18-month-old daughter, who exhibited an overlapping array of features. Features common to all 3 included congenital cataract, microphthalmia, and syndactyly of the second and third toes. In addition, both twins had septate nasal cartilage, high nasal bridge, and a long, narrow face, whereas the daughter showed no facial dysmorphism. One of the twins had a ventricular septal defect, and the daughter had an atrial septal defect. The twins exhibited delayed dentition, persistent primary teeth, and root radiculomegaly; the daughter had delayed primary dentition. One of the twins also had scoliosis and radioulnar synostosis.
In a 14-month-old girl with classic features of syndromic microphthalmia-2 (MCOPS2; 300166), Hilton et al. (2009) identified a heterozygous deletion in the BCOR gene, encompassing exons 13 and 14. PCR amplification and sequencing refined the deletion to 1,410 bp (c.4742-141_4976+821del1410), spanning intron 12 to intron 14 and predicted to result in a premature termination codon (Asp1581GlyfsTer15). The proband's asymptomatic mother, who had a normal panoramic dental x-ray, was found to be mosaic for the mutation.
In a female patient with bilateral congenital cataract and unilateral microphthalmia, Hilton et al. (2009) identified heterozygosity for a 5-bp deletion in the BCOR gene (c.4303_4307delCCATG), causing a frameshift predicted to result in premature termination (Pro1435LeufsTer24). The proband's mother was reported to have a similar phenotype. Further investigation revealed that the proband had had numerous primary teeth removed in the teenage years and also exhibited syndactyly of the second and third toes, suggesting a mild oculofaciocardiodental phenotype (MCOPS2; 300166).
Gross, M. B. Personal Communication. Baltimore, Md. 6/21/2017.
Hilton, E., Johnston, J., Whalen, S., Okamoto, N., Hatsukawa, Y., Nishio, J., Kohara, H., Hirano, Y., Mizuno, S., Torii, C., Kosaki, K., Manouvrier, S., and 25 others. BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects. Europ. J. Hum. Genet. 17: 1325-1335, 2009. [PubMed: 19367324] [Full Text: https://doi.org/10.1038/ejhg.2009.52]
Hoefnagel, D., Keenan, M. E., Allen, F. H. Heredofamilial bilateral anophthalmia. Arch. Ophthal. 69: 760-764, 1963. [PubMed: 13963827] [Full Text: https://doi.org/10.1001/archopht.1963.00960040766015]
Horn, D., Chyrek, M., Kleier, S., Luttgen, S., Bolz, H., Hinkel, G.-K., Korenke, G. C., Riess, A., Schell-Apacik, C., Tinschert, S., Wieczorek, D., Gillessen-Kaesbach, G., Kutsche, K. Novel mutations in BCOR in three patients with oculo-facial-cardio-dental syndrome, but none in Lenz microphthalmia syndrome. Europ. J. Hum. Genet. 13: 563-569, 2005. [PubMed: 15770227] [Full Text: https://doi.org/10.1038/sj.ejhg.5201391]
Huynh, K. D., Fischle, W., Verdin, E., Bardwell, V. J. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 14: 1810-1823, 2000. [PubMed: 10898795]
Junco, S. E., Wang, R., Gaipa, J. C., Taylor, A. B., Schirf, V., Gearhart, M. D., Bardwell, V. J., Demeler, B., Hart, P. J., Kim, C. A. Structure of the polycomb group protein PCGF1 in complex with BCOR reveals basis for binding selectivity of PCGF homologs. Structure 21: 665-671, 2013. [PubMed: 23523425] [Full Text: https://doi.org/10.1016/j.str.2013.02.013]
McGovern, E., Al-Mudaffer, M., McMahon, C., Brosnahan, D., Fleming, P., Reardon, W. Oculo-facio-cardio-dental syndrome in a mother and daughter. Int. J. Oral Maxillofac. Surg. 35: 1060-1062, 2006. [PubMed: 16829040] [Full Text: https://doi.org/10.1016/j.ijom.2006.05.001]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Ng, D., Thakker, N., Corcoran, C. M., Donnai, D., Perveen, R., Schneider, A., Hadley, D. W., Tifft, C., Zhang, L., Wilkie, A. O. M., van der Smagt, J. J., Gorlin, R. J., Burgess, S. M., Bardwell,. V. J., Black, G. C. M., Biesecker, L. G. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nature Genet. 36: 411-416, 2004. [PubMed: 15004558] [Full Text: https://doi.org/10.1038/ng1321]
Oberoi, S., Winder, A. E., Johnston, J., Vargervik, K., Slavotinek, A. M. Case reports of oculofaciocardiodental syndrome with unusual dental findings. Am. J. Med. Genet. 136A: 275-277, 2005. Note: Erratum: Am. J. Med. Genet: 139A: 54 only, 2005. [PubMed: 15957158] [Full Text: https://doi.org/10.1002/ajmg.a.30811]
Ogunye, O. O., Murray, R. F., Jr., Osgood, T. Linkage studies in Lenz microphthalmia. Hum. Hered. 25: 493-500, 1975. [PubMed: 1225823] [Full Text: https://doi.org/10.1159/000152765]
Pierron, G., Tirode, F., Lucchesi, C., Reynaud, S., Ballet, S., Cohen-Gogo, S., Perrin, V., Coindre, J.-M., Delattre, O. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nature Genet. 44: 461-466, 2012. [PubMed: 22387997] [Full Text: https://doi.org/10.1038/ng.1107]
Suzumori, N., Kaname, T., Muramatsu, Y., Yanagi, K., Kumagai, K., Mizuno, S., Naritomi, K., Saitoh, S., Sugiura-Ogasawara, M. Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome. J. Obstet. Gynaec. Res. 39: 1545-1547, 2013. [PubMed: 23815237] [Full Text: https://doi.org/10.1111/jog.12081]