Alternative titles; symbols
HGNC Approved Gene Symbol: GTF2IRD1
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:74,453,906-74,602,605 (from NCBI)
The GTF2IRD1 gene was identified within the chromosomal region on 7q11.23 commonly deleted in Williams syndrome (194050) and is involved in mammalian craniofacial and cognitive development (Tassabehji et al., 2005).
Tassabehji et al. (1999) isolated and characterized a 3.4-kb gene, which they called general transcription factor III (GTF3), which occupies about 140 kb of the region deleted in Williams syndrome. Northern blot analysis showed that the gene is expressed in skeletal muscle and heart, and RT-PCR analysis showed expression in a range of adult tissues with stronger expression in fetal tissues. Part of the conceptual GTF3 protein sequence was found to be almost identical to a slow muscle-fiber enhancer binding protein identified by O'Mahoney et al. (1998) and termed MusTRD1. GTF3 showed significant homology to the 90-amino acid putative helix-loop-helix repeat (HLH) domains of the transcription factor TFII-I (GTF2I; 601679), which maps distal to GTF4 within the Williams syndrome deleted region.
Osborne et al. (1999) identified the same gene, which they termed WBSCR11, by genomic DNA sequence analysis and screening of 2 colon carcinoma cell line cDNA libraries. The cDNA sequence predicts an 895-amino acid protein.
Franke et al. (1999) cloned GTF2IRD1 from cDNA libraries representing several diverse tissues, and they obtained a full-length cDNA by 5-prime RACE of an adult brain cDNA library. They also identified several splice variants arising from exon skipping. The longest deduced protein contains 944 amino acids. In addition to the repeated GTF2I motifs and HLH repeats, Franke et al. (1999) identified a myc (190080)-type HLH dimerization domain, a number of putative phosphorylation sites and N-myristoylation sites, an amidation site, and several putative nuclear localization signals. Northern blot analysis detected expression of GTF2IRD1 in all adult and fetal tissues except leukocytes. The dominant transcript was 3.6 kb long, with sizes ranging from 1.5 kb to 5.0 kb.
By Western blot analysis, Yan et al. (2000) found that endogenous GTF2IRD1, which they designated CREAM1, was expressed at low levels as a 120-kD protein in a variety of human cell lines and tissues. GTF2IRD1 was expressed in the nucleus of transfected cells, and deletion of the C-terminal nuclear localization signal resulted in cytoplasmic expression.
Bayarsaihan and Ruddle (2000) cloned mouse Gtf2ird1, which they designated Ben. The deduced full-length 1,072-amino acid protein contains an N-terminal leucine zipper motif, followed by 6 helix-loop-helix domains, a nuclear localization signal, and a C-terminal serine-rich region. Northern blot analysis detected several Ben transcripts in all mouse tissues examined. Western blot analysis showed several Ben isoforms with apparent molecular masses of 40 to 165 kD.
Osborne et al. (1999) determined that the WBSCR11 gene spans 95 kb of genomic DNA and consists of 26 exons, not including the last noncoding exon.
Franke et al. (1999) determined that the GTF2IRD1 gene contains up to 30 exons and spans about 105 kb. The coding sequence uses 26 exons.
Palmer et al. (2010) determined that the region upstream of the GTF2IRD1 gene contains a well-conserved CCAAT box and 3 canonical GTF2IRD1-recognition sequences (GGATTA), one of which is inverted.
Franke et al. (1999) reported that the GF2IRD1 gene maps within the WBS deletion region on chromosome 7q11.23 and is oriented 5-prime to 3-prime in the centromeric to telomeric orientation.
Tassabehji et al. (1999) tabulated 11 genes in addition to GTF3 that had been mapped to the deleted area of chromosome 7 in classic Williams syndrome.
Lazebnik et al. (2008) stated that the mouse Gtf2ird1 gene maps to a region of chromosome 5 that shares homology of synteny with human chromosome 7.
Yan et al. (2000) determined that GTF2IRD1 interacted with the RB1 protein (614041) in vitro and in vivo. They also showed that full length GTF2IRD1 stimulated transcription of a reporter gene and, by mutation analysis, they localized the activation domain to the N terminus.
Using yeast 1-hybrid analysis, Bayarsaihan and Ruddle (2000) showed that in vitro-translated mouse Ben interacted with an early enhancer upstream of the Hoxc8 (142970) transcription start site.
Ring et al. (2002) characterized the Xenopus homolog of GTF2IRD1, Xwbscr11. They determined that Xwbscr11 binds DNA via selective HLH repeats and interacts with the transcription factor FOXH1 (603621) and the signal transduction molecules Smad2 (601366) and Smad3 (603109) to affect activin (147290)/nodal-mediated induction of the distal element of the Xenopus goosecoid promoter.
Vullhorst and Buonanno (2003) characterized mouse Gtf3 splice variants. They determined that HLH domain 4 is necessary and sufficient for binding the bicoid-like motif of the troponin (191042) enhancer. An isoform that lacks exon 23 and exons 26 through 28 interacted most avidly with the bicoid-like motif. Isoforms that included these exons failed to bind in gel retardation assays. The authors also determined that Gtf3 polypeptides associate with each other via the leucine zipper.
Lazebnik et al. (2008) showed that BEN bound the 8-bp core consensus sequence CAG(C/G)G(C/A)GA, surrounded by G- and C-rich sequences. BEN repressed expression of a reporter gene containing 3 copies of the sequence 5-prime-GGGGGCAGCGACAGCCCCC-3-prime. Knockdown of Ben expression in C2C12 mouse myoblasts enhanced expression of Bmpr1b (603248), Sox4 (184430), En1 (131290), and Fgf15, the mouse ortholog of FGF19 (603891). Chromatin immunoprecipitation analysis followed by quantitative PCR confirmed binding of BEN to Fgf15.
Palmer et al. (2010) found that GTF2IRD1 is subject to negative autoregulation. All isoforms of mouse or human GTF2IRD1 bound 3 canonical GTF2IRD1-binding sites (GGATTA) in the region upstream of the GTF2IRD1 gene. EMSA using artificial DNA probes and in vitro-translated GTF2IRD1 revealed enhanced binding in the presence of 3 GGATTA sites and dimerization of GTF2IRD1 proteins via an N-terminal leucine zipper region. Binding by GTF2IRD1 repressed expression of a reporter gene.
Tassabehji et al. (1999) found that GTF3 was deleted in patients with classic Williams syndrome, but not in patients with partial deletions who had only supravalvular aortic stenosis. They suggested that haploinsufficiency of the GTF3 gene may be the cause of the abnormal muscle fatigability that is characteristic of Williams syndrome.
Tassabehji et al. (2005) reported a rare WBS individual with an atypical deletion, including the GTF2IRD1 gene, showed facial dysmorphism and cognitive deficits that differed from those of classic WBS cases. They proposed a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.
Tassabehji et al. (2005) demonstrated that GTF2IRD1 is involved in mammalian craniofacial and cognitive development. Gtf2ird1-null mice exhibited phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren syndrome; craniofacial imaging revealed abnormalities in both skull and jaws that may arise through misregulation of goosecoid (138890), a downstream target of Gtf2ird1.
Palmer et al. (2010) found that mutant mice lacking Gtf2ird1 exon 2 expressed a mutant Gtf2ird1 transcript. The mutant transcript was expressed at wildtype levels due to escape from nonsense mediated decay and escape from negative autoregulation by Gtf2ird1 itself.
Bayarsaihan, D., Ruddle, F. H. Isolation and characterization of BEN, a member of the TFII-I family of DNA-binding proteins containing distinct helix-loop-helix domains. Proc. Nat. Acad. Sci. 97: 7342-7347, 2000. [PubMed: 10861001] [Full Text: https://doi.org/10.1073/pnas.97.13.7342]
Franke, Y, Peoples, R. J., Francke, U. Identification of GTF2IRD1, a putative transcription factor within the Williams-Beuren syndrome deletion at 7q11.23. Cytogenet Cell Genet. 86: 296-304, 1999. [PubMed: 10575229] [Full Text: https://doi.org/10.1159/000015322]
Lazebnik, M. B., Tussie-Luna, M. I., Roy, A. L. Determination and functional analysis of the consensus binding site for TFII-I family member BEN, implicated in Williams-Beuren syndrome. J. Biol. Chem. 283: 11078-11082, 2008. [PubMed: 18326499] [Full Text: https://doi.org/10.1074/jbc.C800049200]
O'Mahoney, J. V., Guven, K. L., Lin, J., Joya, J. E., Robinson, C. S., Wade, R. P., Hardeman, E. C. Identification of a novel slow-muscle-fiber enhancer binding protein, MusTRD1. Molec. Cell. Biol. 18: 6641-6652, 1998. Note: Erratum: Molec. Cell. Biol. 20: 5361 only, 2000. [PubMed: 9774679] [Full Text: https://doi.org/10.1128/MCB.18.11.6641]
Osborne, L. R., Campbell, T., Daradich, A., Scherer, S. W., Tsui, L.-C. Identification of a putative transcription factor gene (WBSCR11) that is commonly deleted in Williams-Beuren syndrome. Genomics 57: 279-284, 1999. [PubMed: 10198167] [Full Text: https://doi.org/10.1006/geno.1999.5784]
Palmer, S. J., Santucci, N., Widagdo, J., Bontempo, S. J., Taylor, K. M., Tay, E. S. E., Hook, J., Lemckert, F., Gunning, P. W., Hardeman, E. C. Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism. J. Biol. Chem. 285: 4715-4724, 2010. [PubMed: 20007321] [Full Text: https://doi.org/10.1074/jbc.M109.086660]
Ring, C, Ogata, S., Meek, L., Song, J., Ohta, T., Miyazono, K., Cho, K. W. The role of a Williams-Beuren syndrome-associated helix-loop-helix domain-containing transcription factor in activin/nodal signaling. Genes Dev. 16: 820-835, 2002. [PubMed: 11937490] [Full Text: https://doi.org/10.1101/gad.963802]
Tassabehji, M., Carette, M., Wilmot, C., Donnai, D., Read, A. P., Metcalfe, K. A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome. Europ. J. Hum. Genet. 7: 737-747, 1999. [PubMed: 10573005] [Full Text: https://doi.org/10.1038/sj.ejhg.5200396]
Tassabehji, M., Hammond, P., Karmiloff-Smith, A., Thompson, P., Thorgeirsson, S. S., Durkin, M. E., Popescu, N. C., Hutton, T., Metcalfe, K., Rucka, A., Stewart, H., Read, A. P., Maconochie, M., Donnai, D. GTF2IRD1 in craniofacial development of humans and mice. Science 310: 1184-1187, 2005. [PubMed: 16293761] [Full Text: https://doi.org/10.1126/science.1116142]
Vullhorst, D., Buonanno, A. Characterization of general transcription factor 3, a transcription factor involved in slow muscle-specific gene expression. J Biol. Chem. 278: 8370-8379, 2003. [PubMed: 12475981] [Full Text: https://doi.org/10.1074/jbc.M209361200]
Yan, X, Zhao, X., Qian, M., Guo, N, Gong, X., Zhu, X. Characterization and gene structure of a novel retinoblastoma-protein-associated protein similar to the transcription regulator TFII-I. Biochem. J. 345: 749-757, 2000. [PubMed: 10642537]