Alternative titles; symbols
HGNC Approved Gene Symbol: UBTF
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:44,205,040-44,221,304 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Neurodegeneration, childhood-onset, with brain atrophy | 617672 | Autosomal dominant | 3 |
Upstream binding factor (UBF) is a transcription factor required for expression of the 18S, 5.8S, and 28S ribosomal RNAs, along with SL1 (a complex of TBP (600075) and multiple TBP-associated factors or 'TAFs'). Two UBF polypeptides, of 94 and 97 kD, exist in the human (Bell et al., 1988). UBF is a nucleolar phosphoprotein with both DNA binding and transactivation domains. Sequence-specific DNA binding to the core and upstream control elements of the human rRNA promoter is mediated through several HMG boxes (Jantzen et al., 1990).
The mouse Ubf cDNA and gene were cloned by Hisatake et al. (1991). Alternative use of exon 8 produces cDNAs encoding either a 765- or 728-amino acid protein. O'Mahony and Rothblum (1991) identified 2 forms of the Ubtf mRNA in the rat.
Jantzen et al. (1990) cloned human UBF by screening a HeLa cell cDNA library with DNA probes based on tryptic peptides of the protein. They found an open reading frame encoding the 764-amino acid UBF. The authors also characterized DNA binding characteristics of UBF. Chan et al. (1991) cloned the human cDNA by screening an expression library with a specific autoantibody that recognizes nucleolar organizing regions.
Matera et al. (1997) reported that the 2 observed isoforms of UBTF, which differ by 37 amino acids, are generated by alternative splicing.
Toro et al. (2018) noted that the longer UBTF isoform, isoform UBTF1 (or isoform a), regulates ribosomal RNA (rRNA) transcription by RNA polymerase-1, whereas the shorter UBTF isoform, isoform UBTF2 (or isoform b), which lacks exon 8, regulates mRNA transcription by RNA polymerase-2. UBTF can also be regulated by posttranslational modification.
Cell size is strongly dependent on ribosome biogenesis, which is controlled by RNA polymerase I (see 602000). The activity of this polymerase is modulated by a complex of proteins, including UBTF. From experiments with mouse embryonic fibroblasts, Drakas et al. (2004) presented evidence that a nuclear complex forms between IRS1 (147545), UBTF, and PI3K (see 171834), leading to the serine phosphorylation of UBF1 and regulation of rRNA synthesis.
By immunoprecipitation analysis, Shimono et al. (2005) found that MCRS1 (609504) interacted with MI2-beta (CHD4; 603277), RFP (TRIM27; 602165), and UBF. Confocal microscopy demonstrated colocalization of MCRS1, MI2-beta, RFP, and UBF in nucleoli. Chromatin immunoprecipitation assays showed that MCRS1, MI2-beta, and RFP associated with rDNA and were involved in transactivation of ribosomal gene transcription, which could be downregulated by small interfering RNA-mediated downregulation of MCRS1, MI2-beta, and RFP.
Hisatake et al. (1991) showed that the mouse Ubf gene contains 13 exons and spans more than 13 kb.
Jones et al. (1995) mapped the UBTF gene to the BRCA1 region of 17q21 by analyzing genomic clones from that region. They found the gene order to be cen--PPY(167780)--UBTF--EPB3(109270)--GP2B(607759)--tel. Using fluorescence in situ hybridization and radiation hybrid mapping, Matera et al. (1997) mapped the UBTF gene to 17q21.3.
In 7 unrelated patients with childhood-onset neurodegeneration with brain atrophy (CONDBA; 617672), Edvardson et al. (2017) identified a recurrent de novo heterozygous missense mutation in the UBTF gene (E210K; 600673.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of fibroblasts from 1 patient showed significantly increased binding of mutant UBTF to the rDNA promoter and to the 5-prime external transcribed spacer, consistent with a gain-of-function effect. This was associated with significantly increased expression of ribosomal subunit 18S, indicating that E210K UBTF acts as a hyperactive transcription factor. Patient cells showed enlarged nucleoli that were reduced in number per cell. The findings established a link between neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism. Edvardson et al. (2017) suggested that such chromatin dysregulation could have a profound impact on mitosis, DNA repair, and neural cells in particular, since rDNA heterochromatin status is tightly regulated during differentiation and has a broader effect on heterochromatin formation throughout the nucleus. However, the authors emphasized that all data were derived from a single cell line of an affected individual and 1 healthy control.
Toro et al. (2018) identified a recurrent de novo heterozygous E210K mutation in the UBTF gene in 4 unrelated patients with CONDBA. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of patient fibroblasts showed that the mutant protein was expressed normally and showed normal nucleolar localization. However, patient cells had increased expression of pre-rRNA and 18S rRNA compared to controls, suggesting a gain of function. There were also abnormalities in the expression of putative UBTF2 targets. Patient fibroblasts showed increased DNA double-strand breaks, failure of progression to the G2 phase of the cell cycle, and a tendency towards apoptotic cell death. There was a trend for UBTF E210K fibroblasts to harbor fewer nucleoli per nucleus compared to controls, but there was no significant effect of the mutation on nucleolar area. The authors suggested that increased expression of rRNA and nucleolar stress in combination with dysregulation of UBTF2 target genes may cause progressive DNA breaks with an accumulation of damaged DNA, causing neurodegeneration.
Toro et al. (2018) found that pan-neuronal expression of the heterozygous E210K mutation (600673.0001) was lethal in Drosophila. Overexpression of wildtype UBTF1 restricted to the eye resulted in a small-eye phenotype, whereas expression of mutant UBTF in the eye resulted in embryonic lethality in the pupal stage with underdeveloped heads. The findings indicated that increased levels of rRNA is toxic to cells. Toro et al. (2018) noted that homozygous loss of Ubtf is lethal to mice, but the authors observed that heterozygous adult Ubtf +/- mice had only mild motor and behavioral abnormalities compared to wildtype.
In 7 unrelated patients with childhood-onset neurodegeneration with brain atrophy (CONDBA; 617672), Edvardson et al. (2017) identified a recurrent de novo heterozygous c.628G-A transition (c.628G-A, NM_014233.3) in the UBTF gene, resulting in a glu210-to-lys (E210K) substitution at a conserved residue in the second HMG-box homology domain. This residue is followed by 2 lysine residues; thus the mutation would result in a string of 3 lysine residues, conferring a highly positively charged region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Studies of fibroblasts derived from 1 patient showed that the mutation resulted in a gain of function and increased expression of ribosomal subunit 18S.
Toro et al. (2018) identified a recurrent de novo heterozygous E210K mutation in the UBTF gene in 4 unrelated patients with CONDBA. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of patient fibroblasts showed that the mutant protein was expressed normally and showed normal nucleolar localization. However, patient cells had increased expression of pre-rRNA and 18S rRNA compared to controls, suggesting a gain of function. There were also abnormalities in the expression of putative UBTF2 targets. Patient fibroblasts showed increased DNA double-strand breaks, failure of progression to the G2 phase of the cell cycle, and a tendency towards apoptotic cell death. There was a trend for UBTF E210K fibroblasts to harbor fewer nucleoli per nucleus compared to controls, but there was no significant effect of the mutation on nucleolar area.
Bell, S. P., Learned, R. M., Jantzen, H.-M., Tjian, R. Functional cooperativity between transcription factors UBF1 and SL1 mediates human ribosomal RNA synthesis. Science 241: 1192-1197, 1988. [PubMed: 3413483] [Full Text: https://doi.org/10.1126/science.3413483]
Chan, E. K. L., Imai, H., Hamel, J. C., Tan, E. M. Human autoantibody to RNA polymerase I transcription factor hUBF: molecular identity of nucleolus organizer region autoantigen NOR-90 and ribosomal RNA transcription upstream binding factor. J. Exp. Med. 174: 1239-1244, 1991. [PubMed: 1940801] [Full Text: https://doi.org/10.1084/jem.174.5.1239]
Drakas, R., Tu, X., Baserga, R. Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase. Proc. Nat. Acad. Sci. 101: 9272-9276, 2004. [PubMed: 15197263] [Full Text: https://doi.org/10.1073/pnas.0403328101]
Edvardson, S., Nicolae, C. M., Agrawal, P. B., Mignot, C., Payne, K.,Prasad, A. N., Prasad, C., Sadler, L., Nava, C., Mullen, T. E., Begtrup,A., Baskin, B., Powis, Z., Shaag, A., Keren, B., Moldovan, G.-L., Elpeleg,O. Heterozygous de novo UBTF gain-of-function variant is associated with neurodegeneration in childhood. Am. J. Hum. Genet. 101: 267-273, 2017. [PubMed: 28777933] [Full Text: https://doi.org/10.1016/j.ajhg.2017.07.002]
Hisatake, K., Nishimura, T., Maeda, Y., Hanada, K., Song, C.-Z., Muramatsu, M. Cloning and structural analysis of cDNA and the gene for mouse transcription factor UBF. Nucleic Acids Res. 19: 4631-4637, 1991. [PubMed: 1891354] [Full Text: https://doi.org/10.1093/nar/19.17.4631]
Jantzen, H.-M., Admon, A., Bell, S. P., Tjian, R. Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature 344: 830-836, 1990. [PubMed: 2330041] [Full Text: https://doi.org/10.1038/344830a0]
Jones, K. A., Black, D. M., Griffiths, B. L., Solomon, E. Localization of the human RNA polymerase I transcription factor gene (UBTF) to the S17S183 locus on chromosome 17q21 and construction of a long-range restriction map of the region. Genomics 30: 602-604, 1995. [PubMed: 8825649] [Full Text: https://doi.org/10.1006/geno.1995.1283]
Matera, A. G., Wu, W., Imai, H., O'Keefe, C. L., Chan, E. K. L. Molecular cloning of the RNA polymerase I transcription factor hUBF/NOR-90 (UBTF) gene and localization to 17q21.3 by fluorescence in situ hybridization and radiation hybrid mapping. Genomics 41: 135-138, 1997. [PubMed: 9126496] [Full Text: https://doi.org/10.1006/geno.1997.4647]
O'Mahony, D. J., Rothblum, L. I. Identification of two forms of the RNA polymerase I transcription factor UBF. Proc. Nat. Acad. Sci. 88: 3180-3184, 1991. [PubMed: 2014238] [Full Text: https://doi.org/10.1073/pnas.88.8.3180]
Shimono, K., Shimono, Y., Shimokata, K., Ishiguro, N., Takahashi, M. Microspherule protein 1, Mi-2-beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription. J. Biol. Chem. 280: 39436-39447, 2005. [PubMed: 16186106] [Full Text: https://doi.org/10.1074/jbc.M507356200]
Toro, C., Hori, R. T., Malicdan, M. C. V., Tifft, C. J., Goldstein, A., Gahl, W. A., Adams, D. R., Fauni, H. B., Wolfe, L. A., Xiao, J., Khan, M. M., Tian, J., Hope, K. A., Reiter, L. T., Tremblay, M. G., Moss, T., Franks, A. L., Balak, C., C4RCD Researh Group, LeDoux, M. S. A recurrent de novo missense mutation in UBTF causes developmental neuroregression. Hum. Molec. Genet. 27: 691-705, 2018. Note: Erratum: Hum. Molec. Genet. 27: 1310 only, 2018. [PubMed: 29300972] [Full Text: https://doi.org/10.1093/hmg/ddx435]