Alternative titles; symbols
HGNC Approved Gene Symbol: GTF2I
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38) : 7:74,657,718-74,760,692 (from NCBI)
The GTF2I gene encodes a transcription factor (Roy et al., 1997). The protein also negatively regulates agonist-induced calcium entry into cells by interfering with expression of the cation channel TRPC3 (602345) at the plasma membrane (Caraveo et al., 2006).
Bruton tyrosine kinase (BTK; 300300) is essential for B-cell activation. A defect in the BTK gene results in X-linked agammaglobulinemia. Yang and Desiderio (1997) isolated a downstream target of BTK, a protein they designated BAP135 that is associated with the Bruton tyrosine kinase in B cells and is a substrate for phosphorylation by BTK. The investigators used amino acid sequence from the purified protein to identify overlapping expressed sequence tags (ESTs) corresponding to the gene encoding BAP135. The resulting open reading frame predicts a 957-amino acid polypeptide. BAP135, which exhibited no detectable homology to known proteins, contains 6 occurrences of a hitherto undescribed amino acid repeat and 2 motifs, similar to the Src autophosphorylation site, that represent potential targets for tyrosine phosphorylation. Various observations suggested to Yang and Desiderio (1997) that BAP135 may reside downstream of BTK in a signaling pathway originating at the B-cell receptor.
Roy et al. (1997) purified GTF2I from HeLa cell nuclear extracts. Using probes synthesized from the known amino acid sequence, they cloned GTF2I from a Namalwa (Burkitt lymphoma) cDNA library. The 120-kD protein has an N-terminal hydrophobic zipper-like region suggestive of a protein interaction domain, acidic clusters reminiscent of acidic activation domains, and 6 directly repeated 90-residue stretches, each of which possesses a potential helix-loop/span-helix motif. It also contains a consensus site for MAP kinase and several Src autophosphorylation sites. By Northern blot analysis, Roy et al. (1997) detected a 4.7-kb message in HeLa and Namalwa cell lysates. Strong expression of 4.7- and 4.2-kb transcripts were found in heart, brain, skeletal muscle, and pancreas, less in lung, and little in liver and kidney.
Cheriyath and Roy (2000) cloned 4 alternatively spliced variants of GTF2I. GTF2I-delta encodes the previously recognized 957-amino acid protein. Within GTF2I, Cheriyath and Roy (2000) identified a nuclear localization (NLS) signal between amino acid repeats 1 and 2 and another between repeats 4 and 5. The GTF2I-alpha, GTF2I-beta, and GTF2I-gamma variants encode proteins of 977, 978, and 998 amino acids, respectively. These proteins differ from GTF2I-delta and from each other only by the length of an insert between repeat 1 and the first NLS. Western blot analysis detected all endogenous and epitope-tagged GTF2I isoforms predominantly in nuclear cell fractions. Hakre et al. (2006) stated that only the beta and delta isoforms of Gtf2i are expressed in mouse fibroblasts.
Through transfection experiments, Roy et al. (1997) found that GTF2I is capable of binding to both a pyrimidine-rich initiator (Inr) and an E-box for upstream stimulatory factor-1 (USF1; 191523). GTF2I and USF1 can also act synergistically to activate transcription through both Inr and the E-box elements of the adenovirus major late promoter. By in vitro cotranslation followed by coimmunoprecipitation studies, Roy et al. (1997) confirmed direct protein interaction between GTF2I and USF1.
By mutation analysis, Cheriyath and Roy (2000) determined that the first NLS of GTF2I directed the nuclear localization of fluorescence-tagged GTF2I-delta in transfected COS cells. All GTF2I isoforms formed both homomeric and heteromeric interactions when coexpressed or when present endogenously. Heteromeric GTF2I complexes were preferentially found inside the nucleus, and the heteromeric interactions appeared to aid in nuclear translocation. All 4 isoforms bound DNA and possessed similar homomeric transactivation of reporter genes. However, heteromeric complex formation led to differential activation of reporter genes.
Hakimi et al. (2003) identified a family of multiprotein corepressor complexes that function through modifying chromatin structure to keep genes silent. The polypeptide composition of these complexes includes a common core of 2 subunits, HDAC1 (601241)/HDAC2 (605164) and the FAD-binding protein BHC110 (AOF2; 609132). Other subunits of these complexes include ZNF261 (300061), GTF2I, and polypeptides associated with cancer-causing chromosomal translocations.
Caraveo et al. (2006) reported an unanticipated role of TFII-I outside the nucleus as a negative regulator of agonist-induced calcium entry that suppresses surface accumulation of TRPC3 (602345) channels. Inhibition of agonist-induced calcium entry by TFII-I requires phosphotyrosine residues that engage the SH2 (Src homology 2) domains of phospholipase C-gamma (see 172420) and an uninterrupted, pleckstrin homology-like domain that binds the split pleckstrin homology domain of PLC-gamma. Caraveo et al. (2006) concluded that their observations suggest a model in which TFII-I suppresses agonist-induced calcium entry by competing with TRPC3 for binding to PLC-gamma.
Hakre et al. (2006) found endogenous mouse Gtf2i-beta was expressed in the nucleus and was found on the c-fos (FOS; 164810) promoter in resting fibroblasts, but it was absent from the promoter following serum stimulation. In contrast, Gtf2i-delta was largely cytoplasmic in resting cells, but it translocated to the nucleus upon growth factor stimulation, bound the same site on the c-fos promoter, and activated c-fos promoter activity. In addition, activated Gtf2i-delta interacted with Erk1 (MAPK3; 601795)/Erk2 (MAPK1; 176948) in the cytoplasm and imported Erk1/Erk2 to the nucleus, thereby transducing growth factor signaling.
Mammoto et al. (2009) showed that the Rho inhibitor p190RhoGAP (GRLF1; 605277) controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between 2 antagonistic transcription factors, TFII-I and GATA2 (137295), that govern gene expression of the VEGF receptor VEGFR2 (191306). Moreover, this angiogenesis signaling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. Mammoto et al. (2009) suggested that this finding represented the first known functional crossantagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.
By sequence analysis, Perez Jurado et al. (1998) identified the GTF2I gene at 7q11.23.
Williams-Beuren Syndrome
Williams-Beuren syndrome (WBS; 194050) is a neurodevelopmental disorder with multisystemic manifestations caused by heterozygosity for a partial deletion of 7q11.23. The breakpoints cluster within regions located approximately 1 cM at either side of the elastin locus (ELN; 130160). Perez Jurado et al. (1998) characterized a duplicated region near the common deletion breakpoints, which includes a transcribed gene. The centromeric (C) and telomeric (T) copies are almost identical in the duplicated 3-prime portions but diverge at the 5-prime ends. C-specific 4.3-kb mRNA and T-specific 5.4-kb mRNA are widely expressed in embryonic and adult tissues. The telomeric gene gives rise to several tandemly spliced forms and is deleted in all WBS individuals who have documented ELN deletions. Database searches showed that this gene encodes BAP135, a protein phosphorylated by BTK in B cells, as well as the multifunctional transcription factor TFII-I; hence, the gene name GTF2I. The centromeric gene is not deleted in WBS and appears to be a partially truncated expressed pseudogene (GTF2IP1) with no protein product. Both loci map to different genomic clone contigs that also contain other deleted and nondeleted loci. The duplicated region containing GTF2I and GTF2IP1, respectively, is located close to the deletion breakpoints and may predispose to unequal meiotic recombination between chromosome 7 homologs and/or to intrachromosomal rearrangements. Hemizygosity for GTF2I may also contribute to the WBS phenotype.
Most individuals with WBS have a 1.6-Mb deletion in chromosome 7q11.23 that encompasses the elastin gene (ELN; 130160), whereas most families with autosomal dominant supravalvar aortic stenosis (SVAS; 185500) have point mutations in ELN. The overlap of the clinical phenotypes of the 2 conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. To find other genes contributing to the Williams-Beuren syndrome phenotype, Morris et al. (2003) studied 5 families with SVAS who had small deletions in the WBS region. None of the families had mental retardation, but affected family members had the WBS cognitive profile. Although the deletions from the families nearly spanned the WBS region, none had a deletion of FKBP6 (604836) or GTF2I, suggesting that the mental retardation seen in WBS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these 5 families with reports of other individuals with partial deletions of the WBS region strongly implicated GTF2I in the mental retardation of Williams-Beuren syndrome.
Collette et al. (2009) used quantitative RT-PCR to determine the transcriptional level of 14 WBS markers in a cohort of 77 WBS patients and 48 controls, and observed that the parental origin of the deletion contributed to the level of expression of GTF2I independently of age and gender, with significantly lower expression when the single remaining copy was located on the paternally derived chromosome (p = 0.0002). Correlation of expression of GTF2I and some other genes in the WBS region differed between WBS patients and controls, pointing to a regulatory role for the GTF2I gene. Interspecies comparisons suggested that GTF2I may play a key role in normal brain development.
Dai et al. (2009) provided a detailed genotype/phenotype analysis of a 7-year-old girl with WBS resulting from an atypical 7q11.2 deletion (Jarvinen-Pasley et al., 2008). She had some specific features of the disorder, including growth delay, characteristic facies, cardiovascular involvement with pulmonic stenosis and hypertension, delayed growth, and deficits in visual-spatial construction. However, in contrast to the usual findings in WBS, she had normal developmental milestones, comparatively high cognitive function, and did not have the typical delay in language or overly social behavior. By high-resolution oligonucleotide array CGH analysis, multicolor FISH analysis, and PCR analysis of somatic cell hybrids, they showed that the 1.26- to 1.31-Mb deletion included most of the genes in the interval through GTF2IRD1 (604318), but not the GTF2I gene. Neuropsychologic studies showed that the patient had IQ scores 1 to 23 standard deviations above typical WBS children. Dai et al. (2009) postulated that deletion of GTF2I may not play a role in some of the physical aspects of WBS, but may play an important role in some aspects of cognition and social behavior seen in the disorder. Dai et al. (2009) also found no correlation between neurocognitive performance and social behavior among 20 patients with typical WBS, suggesting that the normal social behavior in the atypical patient did not result from better cognition.
Mervis et al. (2012) found that patients with WBS duplication syndrome (609757) had significantly higher levels of separation anxiety (see 607834) compared to patients with WBS and to the general population. Using a parental assessment form with review by a psychologist, Mervis et al. (2012) determined that 8 (29.6%) of 27 children with WBS duplication syndrome had separation anxiety disorder compared to only 9 (4.2%) of 214 patients with WBS. The proportion of WBS duplication patients with the disorder was also significantly higher than in the general population (2.3%). Similar findings were obtained using a second clinical assessment tool. Compared to mice with 1 or 2 copies of the Gtf2i gene, transgenic mice with 3 or 4 copies of the Gtf2i gene showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations (see ANIMAL MODEL). Mervis et al. (2012) postulated that the role of GTF2I as a transcription factor and/or as a regulator of intracellular calcium levels may play a role in the molecular basis of anxiety.
Somatic Mutation in Thymic Epithelial Tumors
Petrini et al. (2014) analyzed 28 thymic epithelial tumors using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970 T-A) in GTF2I at high frequency in type A thymomas (see 274230), a relatively indolent subtype. In a series of 274 thymic epithelial tumors, Petrini et al. (2014) detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I beta and delta isoforms were expressed in thymic epithelial tumors, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively).
By analyzing short-read mapping depth for 159 human genomes, Sudmant et al. (2010) demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kb pairs, ranging from 0 to 48 copies. Sudmant et al. (2010) identified 4.1 million 'singly unique nucleotide' positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identified human-specific expansions in genes associated with brain development, such as GPRIN2 (611240) and SRGAP2 (606524), which have been implicated in neurite outgrowth and branching. Also included were the brain-specific HYDIN2 gene (610813), associated with micro- and macrocephaly; DRD5 (126453), a dopamine D5 receptor; and the GTF2I transcription factors, whose deletion has been associated with visual-spatial and sociability deficits among Williams-Beuren syndrome patients, among others. The data of Sudmant et al. (2010) also revealed extensive population genetic diversity, especially among the genes NPEPPS (606793), UGT2B17 (601903), and NBPF1 (610501), as well as LILRA3 (604818), which is the most highly stratified gene by copy number in the human genome. In addition, Sudmant et al. (2010) detected signatures consistent with gene conversion in the human species.
In mouse pups, separation anxiety can be assessed through ultrasonic vocalizations. Mervis et al. (2012) recorded ultrasonic vocalization in 8-day-old mouse pups with 1 to 4 copies of Gtf2i during a 4-minute separation from their mothers. Transgenic mice with 3 or 4 copies of the Gtf2i gene showed significantly increased maternal separation-induced anxiety compared to mice with 1 or 2 copies of the Gtf2i gene, as measured by ultrasonic vocalizations. During the first minute, mice with 3 or 4 copies of Gtf2i produced between 100 and 120 vocalizations, compared with approximately 50 vocalizations for mice with 2 copies and less than 20 for mice with 1 copy.
Caraveo, G., van Rossum, D. B., Patterson, R. L., Snyder, S. H., Desiderio, S. Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science 314: 122-125, 2006. [PubMed: 17023658] [Full Text: https://doi.org/10.1126/science.1127815]
Cheriyath, V., Roy, A. L. Alternatively spliced isoforms of TFII-I: complex formation, nuclear translocation, and differential gene regulation. J. Biol. Chem. 275: 26300-26308, 2000. [PubMed: 10854432] [Full Text: https://doi.org/10.1074/jbc.M002980200]
Collette, J. C., Chen, X.-N., Mills, D. L., Galaburda, A. M., Reiss, A. L., Bellugi, U., Korenberg, J. R. William's syndrome: gene expression is related to parental origin and regional coordinate control. J. Hum. Genet. 54: 193-198, 2009. [PubMed: 19282872] [Full Text: https://doi.org/10.1038/jhg.2009.5]
Dai, L., Bellugi, U., Chen, X.-N., Pulst-Korenberg, A. M., Jarvinen-Pasley, A., Tirosh-Wagner, T., Eis, P. S., Graham, J., Mills, D., Searcy, Y., Korenberg, J. R. Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays. Am. J. Med. Genet. 149A: 302-314, 2009. [PubMed: 19205026] [Full Text: https://doi.org/10.1002/ajmg.a.32652]
Hakimi, M.-A., Dong, Y., Lane, W. S., Speicher, D. W., Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278: 7234-7239, 2003. [PubMed: 12493763] [Full Text: https://doi.org/10.1074/jbc.M208992200]
Hakre, S., Tussie-Luna, M. I., Ashworth, T., Novina, C. D., Settleman, J., Sharp, P. A., Roy, A. L. Opposing functions of TFII-I spliced isoforms in growth factor-induced gene expression. Molec. Cell 24: 301-308, 2006. [PubMed: 17052463] [Full Text: https://doi.org/10.1016/j.molcel.2006.09.005]
Jarvinen-Pasley, A., Bellugi, U., Reilly, J., Mills, D. L., Galaburda, A., Reiss, A. L., Korenberg, J. R. Defining the social phenotype in Williams syndrome: a model for linking gene, the brain, and behavior. Dev. Psychopathol. 20: 1-35, 2008. [PubMed: 18211726] [Full Text: https://doi.org/10.1017/S0954579408000011]
Mammoto, A., Connor, K. M., Mammoto, T., Yung, C. W., Huh, D., Aderman, C. M., Mostoslavsky, G., Smith, L. E. H., Ingber, D. E. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457: 1103-1108, 2009. [PubMed: 19242469] [Full Text: https://doi.org/10.1038/nature07765]
Mervis, C. B., Dida, J., Lam, E., Crawford-Zelli, N. A., Young, E. J., Henderson, D. R., Onay, T., Morris, C. A., Woodruff-Borden, J., Yeomans, J., Osborne, L. R. Duplication of GTF2I results in separation anxiety in mice and humans. Am. J. Hum. Genet. 90: 1064-1070, 2012. [PubMed: 22578324] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.012]
Morris, C. A., Mervis, C. B., Hobart, H. H., Gregg, R. G., Bertrand, J., Ensing, G. J., Sommer, A., Moore, C. A., Hopkin, R. J., Spallone, P. A., Keating, M. T., Osborne, L., Kimberley, K. W., Stock, A. D. GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region. Am. J. Med. Genet. 123A: 45-59, 2003. [PubMed: 14556246] [Full Text: https://doi.org/10.1002/ajmg.a.20496]
Perez Jurado, L. A., Wang, Y.-K., Peoples, R., Coloma, A., Cruces, J., Francke, U. A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum. Molec. Genet. 7: 325-334, 1998. [PubMed: 9466987] [Full Text: https://doi.org/10.1093/hmg/7.3.325]
Petrini, I., Meltzer, P. S., Kim, I.-K., Lucchi, M., Park, K.-S., Fontanini, G., Gao, J., Zucali, P. A., Calabrese, F., Favaretto, A., Rea, F., Rodriguez-Canales, J., and 10 others. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nature Genet. 46: 844-849, 2014. [PubMed: 24974848] [Full Text: https://doi.org/10.1038/ng.3016]
Roy, A. L., Du, H., Gregor, P. D., Novina, C. D., Martinez, E., Roeder, R. G. Cloning of an Inr- and E-box binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 16: 7091-7104, 1997. [PubMed: 9384587] [Full Text: https://doi.org/10.1093/emboj/16.23.7091]
Sudmant, P. H., Kitzman, J. O., Antonacci, F., Alkan, C., Malig, M., Tsalenko, A., Sampas, N., Bruhn, L., Shendure, J., 1000 Genomes Project, Eichler, E. E. Diversity of human copy number variation and multicopy genes. Science 330: 641-646, 2010. [PubMed: 21030649] [Full Text: https://doi.org/10.1126/science.1197005]
Yang, W., Desiderio, S. BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. Proc. Nat. Acad. Sci. 94: 604-609, 1997. [PubMed: 9012831] [Full Text: https://doi.org/10.1073/pnas.94.2.604]