| Written | 2017-05 | Masato Takimoto, Mao Peizhong |
| Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; takimoto@igm.hokudai.ac.jp (MT); Dept of Cell Developmental and Cancer Biology, School of Medicine and Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Oregon, USA maop@ohsu.edu (MP) |
| Abstract | Review on C2orf3, with data on DNA, on the protein encoded, and where the gene isimplicated. |
| Keywords | post-splicing, turnover of mRNA, lariat intron, dyslexia |
| Identity |
| Alias_names | TCF9 |
| C2orf3 | |
| transcription factor 9 (binds GC-rich sequences) | |
| chromosome 2 open reading frame 3 | |
| Alias_symbol (synonym) | DNABF |
| GCF | |
| Other alias | GCFC2?GC-rich sequence DNA-binding factor 2 |
| HGNC (Hugo) | GCFC2 |
| LocusID (NCBI) | 6936 |
| Atlas_Id | 54327 |
| Location | 2p12 [Link to chromosome band 2p12] |
| Location_base_pair | Starts at 75662706 and ends at 75710985 bp from pter ( according to hg19-Feb_2009) [Mapping GCFC2.png] |
 | |
| Structural Relation among C2orf3, GCF and GCF2. GCF is an artificial cDNA composed of GCF2 and C2orf3 | |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| Note | C2orf3 gene was discovered as a C-terminal side of GCF cDNA, which is an artificial chimeric one (Kageyama and Pastan, 1989;Takimoto et al., 1999) . As C2orf3 protein is a factor that plays a role in splicing of mRNA (Yoshimoto et al., 2014) and the protein encoded by a N-terminal side of GCF cDNA, which is a bona fide transcriptional repressor termed GCF2, binds to the GC rich element of DNA (Reed et al., 1998), the nomenclature of this gene as GCFC2 is inappropriate. Major data bases, such as provided by University of California Santa Cruz (UCSC), National Center for Biotechnology Information (NCBI) and Hugo Gene Nomenclature Committee (HGNC), use GCFC2 to describe this gene. For example, UCSC genome browser describes this gene as GCFC2, which is present next to MRP19 gene in the chromosomal 2p12 region (Anthoni et al., 2007). As C2orf3 does not bind to the GC-rich sequence (Takimoto et al., 1999), the use of the term GCFC2 for this gene is misleading and we think it should not be used. |
| DNA/RNA |
| Description | Genomic DNA Genomic size of DNA is about 50 kbp and consists of 17 exons. > cDNA GCF was originally discovered as a gene that encodes a transcriptional repressor that binds to a GC-rich sequence of the regulatory regions of human EGF-R gene (Kageyama and Pastan, 1989). However, a following study showed that GCF cDNA is an artificial fusion molecule between two different cDNAs; The 5' side of the cDNA encodes a highly basic region with the sequence-specific binding activity to the GC-rich region and the 3' side encodes most of C2orf3 protein (Takimoto et al., 1999). Reed et al. cloned a full length of the former cDNA that has transcriptional repressor activity with the sequence-specific DNA binding ability, and named this cDNA as GCF2. Following studies had confirmed the transcriptional repressive activity of GCF2 ( Shibutani M et al., 1998: Khachigian LM et al., 1999). The full length of C2orf3 cDNA was cloned and its sequence was determined. The cDNA is composed of 2661 nucleotides and encodes a protein of 781 amino acids. The encoded protein does not contain the highly basic region of the published GCF and has no sequence-specific DNA binding activity to the GC-rich sequence (Takimoto et al., 1999) cDNA sequence: ( GenBank : AB026911 ) GGGCGGGCACTGAAGCTGCGGCTTGCGGTTCAGCGGGTTCTAGGGCGCCGGGCGCTCGGGCCTCGGCCATGGCTCACAGGCCGAAAAGGACTTTTCGGCA GCGCGCGGCTGATTCCAGCGACAGCGATGGCGCCGAGGAGTCGCCTGCTGAGCCTGGGGCGCCGAGGGAACTTCCGGTCCCGGGTTCTGCGGAGGAAGAG CCGCCCTCTGGAGGAGGCCGCGCGCAGGTGGCGGGACTGCCCCACCGGGTTCGGGGCCCTCGTGGCCGGGGCCGGGTCTGGGCGAGCTCCCGGCGTGCCA CCAAAGCGGCTCCCCGCGCGGACGAAGGCTCAGAATCCAGAACCCTTGATGTGTCCACAGATGAAGAGGATAAAATACATCACTCCTCAGAAAGTAAGGA TGATCAGGGTTTGTCTTCTGACAGTTCTAGCTCTCTTGGAGAAAAAGAACTTTCATCAACAGTTAAGATCCCAGATGCAGCTTTTATTCAGGCAGCCCGC AGAAAACGTGAATTGGCCAGGGCCCAAGATGACTATATTTCTTTGGATGTACAACATACCTCCTCCATCTCTGGTATGAAGAGAGAGAGCGAAGATGACC CTGAGAGTGAGCCTGATGACCATGAAAAGAGAATACCATTTACTCTAAGACCTCAAACACTTAGACAAAGGATGGCTGAGGAATCAATAAGCAGAAATGA AGAAACAAGTGAAGAAAGTCAGGAAGATGAAAAGCAAGATACTTGGGAACAACAGCAAATGAGGAAAGCAGTTAAAATCATAGAGGAAAGAGACATAGAT CTTTCCTGTGGCAGTGGATCTTCAAAAGTGAAGAAATTTGATACTTCCATTTCATTTCCGCCAGTAAATTTAGAAATTATAAAGAAGCAATTAAATACTA GATTAACATTACTACAGGAAACTCACCGCTCACACCTGAGGGAGTATGAAAAATACGTACAAGATGTCAAAAGCTCAAAGAGTACCATCCAGAACCTAGA GAGTTCATCAAATCAAGCTCTAAATTGTAAATTCTATAAAAGCATGAAAATTTATGTGGAAAATTTAATTGACTGCCTTAATGAAAAGATTATCAACATC CAAGAAATAGAATCATCCATGCATGCACTCCTTTTAAAACAAGCTATGACCTTTATGAAACGCAGGCAAGATGAATTAAAACATGAATCAACGTATTTAC AACAGTTATCACGCAAAGATGAGACATCCACAAGTGGAAACTTCTCAGTAGATGAAAAAACTCAGTGGATTTTAGAAGAGATTGAATCTCGAAGGACAAA AAGAAGACAAGCAAGGGTGCTTTCTGGGAATTGTAACCATCAGGAAGGAACATCTAGTGATGATGAACTGCCTTCAGCAGAGATGATTGACTTCCAAAAA AGCCAAGGTGACATTTTACAGAAACAGAAGAAAGTTTTTGAAGAAGTGCAAGATGATTTTTGTAACATCCAGAATATTTTGTTGAAATTTCAGCAATGGC GAGAAAAGTTTCCTGACTCCTATTATGAAGCTTTCATTAGTTTATGCATACCAAAGCTTTTAAATCCCCTAATACGAGTTCAGTTGATTGATTGGAATCC TCTTAAGTTGGAATCCACAGGTTTAAAAGAGATGCCATGGTTCAAATCTGTAGAAGAATTTATGGATAGCAGTGTAGAAGATTCAAAGAAGGAAAGTAGT TCAGATAAAAAAGTCTTGTCTGCAATCATCAACAAAACAATTATTCCCCGACTTACAGACTTTGTAGAATTCCTTTGGGATCCTTTGTCAACCTCACAGA CAACAAGTTTAATAACACATTGCAGAGTGATTCTTGAAGAACATTCCACTTGTGAAAATGAAGTTAGTAAAAGCAGACAGGATTTACTTAAATCCATTGT TTCAAGAATGAAAAAGGCAGTAGAAGATGATGTTTTTATTCCTCTGTATCCAAAGAGTGCTGTAGAAAACAAAACATCACCTCATTCAAAGTTCCAAGAA AGACAGTTCTGGTCAGGCCTAAAGCTCTTCCGCAATATTCTTCTTTGGAATGGACTCCTTACAGATGACACCTTGCAAGAACTAGGACTAGGGAAGCTGC TAAATCGTTACCTTATTATAGCACTTCTCAATGCCACACCTGGGCCAGATGTGGTTAAAAAGTGCAACCAGGTAGCAGCATGTCTACCAGAAAAATGGTT TGAAAATTCTGCCATGAGGACATCTATTCCACAGCTAGAAAACTTCATTCAGTTTTTATTGCAGTCTGCACATAAATTATCTAGAAGTGAATTCAGGGAT GAAGTCGAAGAAATAATTCTTATTTTGGTGAAAATAAAAGCTTTGAATCAAGCAGAATCCTTCATAGGAGAGCATCACCTAGACCATCTTAAATCACTAA TTAAAGAAGATTGAATAAACTTTATTGGAAAATGCTAAAATTTTAATATAGTTACACTCAGTTCCTTTGTTTGAGAAGAAGCTGGTGCCTCTCTCTTCTT TATTCCCTGTAATAGAAGGTAGGATTTGAAAAAAAGCAGGACTCCACCTCTGTATTCCCCCGTGCTTTACCTTCTGGCATCATGAAAAGCTGCCATGATT CTGTGGTGTTCTAAGGAATTAAATGCACTGGAGCTTTAAGAGCTCAACGTGTTTCCCTTTG |
| Transcription | It is suggested that MRPL1 gene which is located closely to C2orf3 with head-head orientation and that they are co-regulated (Anthoni et al., 2007). There are several alternative spliced forms for mRNA expression: The initial report on a cDNA that encompass the full coding region is 2661bp in length (Takimoto et al., 1999). |
| Protein |
| Description | Encodes 781 amino acids Amino acid sequence: (Uniprot : P16383) MAHRPKRTFRQRAADSSDSDGAEESPAEPGAPRELPVPGSAEEEPPSGGGRAQVAGLPHRVRGPRGRGRVWASSRRATKAAPRADEGSESRTLDVSTDEE DKIHHSSESKDDQGLSSDSSSSLGEKELSSTVKIPDAAFIQAARRKRELARAQDDYISLDVQHTSSISGMKRESEDDPESEPDDHEKRIPFTLRPQTLRQ RMAEESISRNEETSEESQEDEKQDTWEQQQMRKAVKIIEERDIDLSCGSGSSKVKKFDTSISFPPVNLEIIKKQLNTRLTLLQETHRSHLREYEKYVQDV KSSKSTIQNLESSSNQALNCKFYKSMKIYVENLIDCLNEKIINIQEIESSMHALLLKQAMTFMKRRQDELKHESTYLQQLSRKDETSTSGNFSVDEKTQW ILEEIESRRTKRRQARVLSGNCNHQEGTSSDDELPSAEMIDFQKSQGDILQKQKKVFEEVQDDFCNIQNILLKFQQWREKFPDSYYEAFISLCIPKLLNP LIRVQLIDWNPLKLESTGLKEMPWFKSVEEFMDSSVEDSKKESSSDKKVLSAIINKTIIPRLTDFVEFLWDPLSTSQTTSLITHCRVILEEHSTCENEVS KSRQDLLKSIVSRMKKAVEDDVFIPLYPKSAVENKTSPHSKFQERQFWSGLKLFRNILLWNGLLTDDTLQELGLGKLLNRYLIIALLNATPGPDVVKKCN QVAACLPEKWFENSAMRTSIPQLENFIQFLLQSAHKLSRSEFRDEVEEIILILVKIKALNQAESFIGEHHLDHLKSLIKED |
| Expression | C2orf3 protein with molecular weight of 89 kD are observed in human cancer cell line, and localizes in nucleoplasm and nucleolus. |
| Function | C2orf3 plays a role in pre-mRNA splicing, by forming a complex with DHX15 (hPrp43) and TFIP11 (Yoshimoto et al., 2014). As these proteins are present in post-splicing intron complex, C2orf3 protein may play a role in post-splicing turnover of mRNA. The study with and antibody specific to C2ofr3 protein showed that this protein is present nucleoplasm and nucleoli. After splicing reaction, pre-mRNA releases intron RNA complex, which contains uridine-rich small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) PRPF19complex, hnRNP proteins and TFIP11. A RNA helicase hPrp43 removes the several factors from the complex, leaving lariat RNA intron, which is then subject to linearization by a debranching enzyme DBR1 (Wen et al., 2008; Yoshimoto et al., 2009).C2orf3 protein was shown to form a complex with tuftelin-interacting protein (TFIP11) and hPrp43, which play a role in post-splicing turnover of mRNA. Through its amino terminal, TFIP11 binds to a RNA helicase hPrp43 that plays a role in the dissociation of snRNAs from a lariat intron in vitro. C2orf3 preferentially associates with lariat intron in the splicing reaction and C2orf3-deleted nuclear extracts showed a significant repression of splicing of pre-mRNA in vitro (Yoshimoto et al., 2014). The presence of C2orf3 protein in nucleoli suggest a potential role in rRNA processing/or nucleoli structure (Yoshimoto et al., 2014). |
| Implicated in |
| Note | Although it is not conclusive, C2orf3 is suggested to be a causing gene for dyslexia. |
| Entity | Dyslexia |
| Note | The locus containing the C2orf3 gene on Chromosome 2p12 has been shown to link to dyslexia. It had been reported that the genomic regions responsive for human dyslexia, such DYXC1/EKN1, KIAA0319 and DCDC, and RUBO1, are located on human chromosome 15, 6 and 3, respectively (McGrath et al., 2006). In 1999, It was shown that a new region for dyslexia, DYX3, on human chromosome 2 was identified (Fagerheim et al., 1999). Subsequently, a study on Finnish and German families disclosed that DYX3 was present on chromosome 2p12, spanning 157 kbp. It was shown that there are only three genes, FLJ1339, MRPL1 and C2ORF3, in this region and that the latter two genes are closely located with positions in a head-to-head manner respective for transcriptional orientation, suggesting that both genes are transcriptionally co-regulated (Anthoni et al., 2007). Further analyses on several affected families revealed an overlapping region with risk haplotype within the 157 kbp region, delineating to 16 kbp, which located in an intergenic region between FLJ1339 and MRPL1/C2ORF3 genes. There is no SNP marker in the coding regions of MRPL1 and C2ORF3 genes by which coding change correlated with dyslexia, and the expressions of both genes are significant lower in carriers with risk haplotype compared with non-carriers. These results suggested that the 16 kbp region plays a role for transcriptional regulatory element and mutation in this element might lead to reduced expression of the genes, which could be a cause of dyslexia. While the expression of FLJ1339 in human brain, the expressions of MRPL1/C2ORF3 are high and significantly correlated with those of other dyslexia candidate genes of whichexpressions are also high in brain. Especially, the expression of C2ORF3 was correlated across the different parts of brain with those of other dyslexia candidate genes, DYXC1, RUBO1 and DCDC2 (Anthoni et al., 2007). Neuroimaging analyses revealed a significant association between a SNP marker and white matter volume of the posterior parts of the corpus callosum and cingulum (Scerri et al., 2012). In contrary to the studies described above, the studies on the populations of Australia and Inida showed non-significant association for the SNP marker for MRPL1/C2ORF3 with dyslexia (Paracchini et al., 2011 : Venkatesh et al., 2013). |
| To be noted |
| Previouly described GCF cDNA is an artificial fusion molecule between two different cDNAs, in which the 3' side of the molecule is derived from C2orf3 cDNA. |
| Bibliography |
| A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia |
| Anthoni H, Zucchelli M, Matsson H, Müller-Myhsok B, Fransson I, Schumacher J, Massinen S, Onkamo P, Warnke A, Griesemann H, Hoffmann P, Nopola-Hemmi J, Lyytinen H, Schulte-Körne G, Kere J, Nöthen MM, Peyrard-Janvid M |
| Hum Mol Genet 2007 Mar 15;16(6):667-77 |
| PMID 17309879 |
| A new gene (DYX3) for dyslexia is located on chromosome 2 |
| Fagerheim T, Raeymaekers P, Tønnessen FE, Pedersen M, Tranebjaerg L, Lubs HA |
| J Med Genet 1999 Sep;36(9):664-9 |
| PMID 10507721 |
| Molecular cloning and characterization of a human DNA binding factor that represses transcription |
| Kageyama R, Pastan I |
| Cell 1989 Dec 1;59(5):815-25 |
| PMID 2556218 |
| GC factor 2 represses platelet-derived growth factor A-chain gene transcription and is itself induced by arterial injury |
| Khachigian LM, Santiago FS, Rafty LA, Chan OL, Delbridge GJ, Bobik A, Collins T, Johnson AC |
| Circ Res 1999 Jun 11;84(11):1258-67 |
| PMID 10364563 |
| Breakthroughs in the search for dyslexia candidate genes |
| McGrath LM, Smith SD, Pennington BF |
| Trends Mol Med 2006 Jul;12(7):333-41 |
| PMID 16781891 |
| Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population |
| Paracchini S, Ang QW, Stanley FJ, Monaco AP, Pennell CE, Whitehouse AJ |
| Genes Brain Behav 2011 Mar;10(2):158-65 |
| PMID 20846247 |
| Molecular cloning and characterization of a transcription regulator with homology to GC-binding factor |
| Reed AL, Yamazaki H, Kaufman JD, Rubinstein Y, Murphy B, Johnson AC |
| J Biol Chem 1998 Aug 21;273(34):21594-602 |
| PMID 9705290 |
| The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure |
| Scerri TS, Darki F, Newbury DF, Whitehouse AJ, Peyrard-Janvid M, Matsson H, Ang QW, Pennell CE, Ring S, Stein J, Morris AP, Monaco AP, Kere J, Talcott JB, Klingberg T, Paracchini S |
| PLoS One 2012;7(11):e50321 |
| PMID 23209710 |
| Transcriptional down-regulation of epidermal growth factor receptors by nerve growth factor treatment of PC12 cells |
| Shibutani M, Lazarovici P, Johnson AC, Katagiri Y, Guroff G |
| J Biol Chem 1998 Mar 20;273(12):6878-84 |
| PMID 9506991 |
| Molecular analysis of the GCF gene identifies revisions to the cDNA and amino acid sequences(1) |
| Takimoto M, Mao P, Wei G, Yamazaki H, Miura T, Johnson AC, Kuzumaki N |
| Biochim Biophys Acta 1999 Oct 6;1447(1):125-31 |
| Lack of association between genetic polymorphisms in ROBO1, MRPL19/C2ORF3 and THEM2 with developmental dyslexia |
| Venkatesh SK, Siddaiah A, Padakannaya P, Ramachandra NB |
| Gene 2013 Oct 25;529(2):215-9 |
| PMID 23954868 |
| TFIP11 interacts with mDEAH9, an RNA helicase involved in spliceosome disassembly |
| Wen X, Tannukit S, Paine ML |
| Int J Mol Sci 2008 Nov;9(11):2105-13 |
| PMID 19165350 |
| Identification of a novel component C2ORF3 in the lariat-intron complex: lack of C2ORF3 interferes with pre-mRNA splicing via intron turnover pathway |
| Yoshimoto R, Okawa K, Yoshida M, Ohno M, Kataoka N |
| Genes Cells 2014 Jan;19(1):78-87 |
| PMID 24304693 |
| Citation |
| This paper should be referenced as such : |
| Takimoto M, Peizhong M |
| C2orf3; |
| Atlas Genet Cytogenet Oncol Haematol. in press |
| On line version : http://AtlasGeneticsOncology.org/Genes/C2orf3ID54327ch2p12.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Feb 28 13:49:16 CET 2018 |
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