Alternative titles; symbols
HGNC Approved Gene Symbol: BDP1
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38) : 5:71,455,651-71,578,288 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.2 | ?Deafness, autosomal recessive 112 | 618257 | Autosomal recessive | 3 |
Using a cDNA walking strategy, Kelter et al. (2000) cloned overlapping partial sequences of TFNR from fetal brain and spinal cord libraries. The deduced 2,254-amino acid protein has a calculated molecular mass of 250 kD. All cDNAs isolated from one fetal brain cDNA library lacked exon 15 resulting in a truncated protein of 796 amino acids. The TFNR protein is highly hydrophilic. It contains a 55-amino acid motif that is repeated as 6 highly conserved and 3 less well-conserved copies encoded by exon 17. It also contains a bipartite nuclear localization signal, a DNA-ligase A1 ATP-dependent (126391) binding site, and a second bipartite nuclear localization signal in the C terminus. Sequence comparison with the first 11 exons of mouse Tfnr, encoding 545 amino acids, indicated 77% identity to the human TFNR protein. A stretch of over 300 amino acids of human TFNR showed 29% identity with the yeast TFC5 protein, a component of the TFIIIB transcription initiation complex. Northern blot analysis detected weak expression of 9.5-, 3.1-, and 1.6-kb transcripts in all tissues examined, and a 1.9-kb transcript expressed only in brain. Analysis of mRNAs from several brain areas showed a strong signal at 9.5 and 1.9 kb in cerebellum, and a weak signal in all other brain areas. Western blot analysis of fetal and adult human tissues showed 5 bands ranging from 55 to 250 kD. Immunofluorescent localization of TFNR in HeLa cells revealed a punctate nuclear staining pattern.
Schramm et al. (2000) also cloned BDP1, which they called hB-double prime, and found that the protein has several potential phosphorylation sites. Schramm et al. (2000) isolated 2 variants, one of which is likely to be a splice variant. The other variant contains an insertion that results in the replacement of the last 21 amino acids with 5 different amino acids. Western blot analysis of HeLa cells showed BDP1 bands at about 160 and 250 kD.
Girotto et al. (2013) analyzed Bdp1 expression in the mouse inner ear at postnatal day 5 and observed clear expression in capillaries of the stria vascularis as well as in mesenchyme-derived cells and the extracellular matrix surrounding the cochlear duct, including the spiral ligament and basilar membrane. Analysis of immunohistochemical labeling patterns suggested that Bdp1 was expressed in endothelial cells of the stria vascularis.
Kelter et al. (2000) determined that the TFNR gene contains 32 exons and spans about 80 kb.
By FISH, Kelter et al. (2000) mapped the TFNR gene to chromosome 5q13. Further analysis of this region indicated that TFNR lies just outside the repeated SMA1 (253300) region. Sequencing of a mouse BAC clone revealed a head-to-head orientation between the Tfnr and Serf1 (603011) genes.
With use of anti-BDP1 antibodies in in vitro transcription reactions, Schramm et al. (2000) determined that BPD1 is required for transcription from the Ad2 VAI and human U6 (180692) RNA polymerase III (pol III; see 606007) promoters. By chromatin immunoprecipitation assays, they also found that BDP1 binds the U6 promoter region in vivo, further suggesting that BDP1 is part of the U6 initiation complex.
Using cross-linking experiments in S. cerevisiae, Hu et al. (2015) validated that the Bdp1 SANT domain interacts with the C terminus of Brf1 (604902) and functions in the formation of the pol III preinitiation complex (PIC) for transcription. Hu et al. (2015) also identified another Brf1-binding site, termed Bdp1 region II, upstream of the SANT domain, which functions as a structural domain for interactions with Brf1 and the C128 subunit (614366) of pol III. Functional analyses indicated that Bdp1 region II is involved in a network of protein interactions following PIC formation. Additional studies showed that Bdp1 region II interacts with the N-terminal half of Brf1 and C128 and the C-terminal domain of C37 in the pol III active site cleft.
Gouge et al. (2017) determined the crystal structure of the human transcription factor IIIB (TFIIIB) complex and found that BDP1 interacts at the interface between the DNA region immediately upstream of the TATA box, the TBP (600075) N-terminal stirrup, and the high-affinity TBP-binding site at the C-terminal end of BRF2 (607023). The BDP1 linker, the N-terminal region flanking the SANT domain, spans the minor groove of the bound DNA and is inserted between the 2 Brf2 cyclin repeats, thereby playing a role in promoter opening. Addition of BDP1 to the BRF2-TBP-DNA complex had no effect on the bending state of the DNA but increased the estimated lifetime of the complex, resulting in extremely stable complexes bound to the DNA. Functional studies demonstrated that the N-terminal and C-terminal regions of BDP1 are capable of binding to the upstream factor SNAPc (see 600591) and that these interactions are essential in driving pol III transcription. The authors proposed that, during pol III transcription initiation, BDP1 stimulates the transition from a closed to an open PIC, likely through an allosteric mechanism involving RNA pol III subunits.
In a consanguineous Qatari family with postlingual progressive sensorineural hearing loss mapping to chromosome 5q13 (DFNB112; 618257), Girotto et al. (2013) identified homozygosity for a nonstop mutation in the BDP1 gene (X2625E; 607012.0001). The mutation segregated fully with disease in the family and was not found in 66 Qatari controls, although it was present at low frequency in public variant databases.
In 4 sibs from a consanguineous Qatari family with postlingual progressive sensorineural hearing loss (DFNB112; 618257), Girotto et al. (2013) identified homozygosity for a c.7873T-G transversion (c.7873T-G, NM_018429) in the BDP1 gene, causing a ter2625-to-glu (X2625E) substitution resulting in lengthening of the protein by 11 additional codons (Ter2625GluextTer11). Their unaffected parents and 1 unaffected sib were heterozygous for the mutation, which was not found in 66 Qatari, 26 Italian, or 3 Omani controls. However, the variant was present at low minor allele frequencies in the ESP6500 (MAF, 0.0007), 1000 Genomes Project (MAF, 0.0009), and the dbSNP (build 137) (MAF, 0.004) databases.
Girotto, G., Abdulhadi, K., Buniello, A., Vozzi, D., Licastro, D., d'Eustacchio, A., Vuckovic, D., Alkowari, M. K., Steel, K. P., Badii, R., Gasparini, P. Linkage study and exome sequencing identify a BDP1 mutation associated with hereditary hearing loss. PLoS One 8: e80323, 2013. Note: Electronic Article. [PubMed: 24312468] [Full Text: https://doi.org/10.1371/journal.pone.0080323]
Gouge, J., Guthertz, N., Kramm, K., Dergai, O., Abascal-Palacios, G., Satia, K., Cousin, P., Hernandez, N., Grohmann, D., Vannini, A. Molecular mechanisms of Bdp1 in TFIIIB assembly and RNA polymerase III transcription initiation. Nature Commun. 8: 130, 2017. Note: Electronic Article. [PubMed: 28743884] [Full Text: https://doi.org/10.1038/s41467-017-00126-1]
Hu, H.-L., Wu, C.-C., Lee,, J.-C., Chen, H.-T. A region of Bdp1 necessary for transcription initiation that is located within the RNA polymerase III active site cleft. Molec. Cell. Biol. 35: 2831-2840, 2015. [PubMed: 26055328] [Full Text: https://doi.org/10.1128/MCB.00263-15]
Kelter, A.-R., Herchenbach, J., Wirth, B. The transcription factor-like nuclear regulator (TFNR) contains a novel 55-amino-acid motif repeated nine times and maps closely to SMN1. Genomics 70: 315-326, 2000. [PubMed: 11161782] [Full Text: https://doi.org/10.1006/geno.2000.6396]
Schramm, L., Pendergrast, P. S., Sun, Y., Hernandez, N. Different human TFIIB activities direct RNA polymerase III transcription from TATA-containing and TATA-less promoters. Genes Dev. 14: 2650-2663, 2000. [PubMed: 11040218] [Full Text: https://doi.org/10.1101/gad.836400]