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OTX2 (orthodenticle homeobox 2)

Identity

Other namesMCOPS5
MGC45000
HGNC (Hugo) OTX2
LocusID (NCBI) 5015
Location 14q22.3
Location_base_pair Starts at 57267425 and ends at 57277194 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Chr14:57267427-57277184 (isoform a),
Chr14:57267427-57277097 (isoform b).
From plus strand: C14orf101, OTX2, EXOC5, MUDENG.

DNA/RNA

Description Total gene sequence: 9757 bp.
Transcription From minus strand. Isoform a: 5 exons, 4 introns; isoform b: 3 exons, 2 introns.
Isoform a: Full-length unspliced transcript: 9757 bp; spliced transcript: 2209 bp;
Isoform b: Full-length unspliced transcript: 9670 bp; spliced transcript: 2082 bp.
Pseudogene OTX2P1 located at 9q21.

Protein

Note Isoforms a and b share the same coding exons, therefore both isoforms encode full-length (289 amino acid) Otx2 protein.
 
  Otx2 protein domains. Domains were defined based on sequence conservation and, when possible, functional analysis as described in Chau et al., 2000 and Chatelain et al., 2006. Conserved OTX family domain identified in the CDD database (Marchler-Bauer et al., 2009). Domain abbreviations and boundaries are as follows: HD: Paired-class homeobox domain, spans amino acids (aa) 37-97; NRS: nuclear retention signal, spans aa 117-146; grey box: WSP domain, spans aa 150-159; OTX: OTX family domain, spans aa 178-243; TA: transactivation domain, comprised of two separate transactivation motifs spanning aa 255-267 and aa 273-285; b: basic regions (aa 36-42, aa 89-94, and aa 107-114); Q: polyglutamine repeat (aa 95-101).
Description 289 amino acids, see diagram for domain organization.
Expression Rostral neural tube (mid-late gestation; Larsen et al., 2010), hippocampus, cerebellar rhombic lip, choroid plexus (Larsen et al., 2010), retinal pigment epithelium (Glubrecht et al., 2009; Larsen et al., 2009). Characterized in rodents: epiblast (Fossat et al., 2006), anterior neural ectoderm and anterior visceral endoderm (Fossat et al., 2006), external granular layer of the postnatal cerebellum (Frantz et al., 1994), posterior lobes of the adult cerebellum (Fossat et al., 2006).
Localisation Predominately nuclear but in some cell types can be retained in the cytoplasm (Baas et al., 2000) as well as transferred from cell to cell (Sugiyama et al., 2008).
Function Homeobox transcription factor, binds the DNA sequence TAATCC (Chatelain et al., 2006). OTX2 plays a critical role in anteroposterior patterning of the embryo (Matsuo et al., 1995), anterior neuroectoderm formation (Acampora et al., 1995), neuronal differentiation in various CNS compartments (Vernay et al., 2005; Omodei et al., 2008), and experience-induced plasticity (Sugiyama et al., 2009).
Homology Shares sequence homology and general domain organization with OTX family members Otx1 and Crx.

Mutations

Germinal Dominant-inherited OTX2 mutations exhibiting variable penetrance have been associated with developmental defects of the eye (Ragge et al., 2005; Wyatt et al., 2008; see the "Implicated in" section below for further discussion) and pituitary (Diaczok et al., 2008) as well as recurrent seizure disorders (Ragge et al., 2005). None associated with hereditary tumor predisposition syndromes.
Somatic None detected in medulloblastoma.

Implicated in

Entity Pediatric CNS cancer (medulloblastoma)
Prognosis 5-year survival rates average 50-60%; predictors of poor outcome include young age (younger than 3 years old) and presence of metastases. OTX2 copy number gain has been associated with shorter survival (Adamson et al., 2010).
Cytogenetics Various broad and focal copy number changes have been identified in medulloblastoma (reviewed in: Northcott et al., 2010), whereas OTX2 is the most common target of focal copy number gain in the medulloblastoma genome (Adamson et al., 2010).
Oncogenesis Otx2 is overexpressed in the majority (~74%) of medulloblastomas (Adamson et al., 2010). A subset of these tumors (~21%) harbor copy number gains of the OTX2 genomic locus; the mechanism of Otx2 overexpression in the remaining tumors remains unidentified. Otx2 is distinctly overexpressed in Shh-independent medulloblastomas (i.e. tumor subtypes not expressing gene signatures of Shh pathway activation; Adamson et al., 2010). Otx2 has been implicated in medulloblastoma tumor progression and is required for tumor maintenance. One mechanism of Otx2 oncogenic activity is transcriptional activation of MYC (Adamson et al., 2010).
  
Entity Retinoblastoma
Cytogenetics Secondary events cooperating with loss of Rb gene function have remained elusive. However, genomewide copy number analysis has revealed recurrent regions of gain or loss at the megabase resolution, and chromosome 14 aberrations have indeed been described (Zielinski et al., 2005).
Oncogenesis Considering the restricted expression pattern of OTX2 mRNA in adult tissues (Boon et al., 2002) and the well-established oncogenic function of Otx2 in medulloblastomas (Adamson et al., 2010), expression of Otx2 in retinoblastoma may indicate a role for this gene in retinoblastoma pathogenesis (Glubrecht et al., 2009). Interestingly, Otx2 is expressed in the most undifferentiated compartments of retinoblastomas (Glubrecht et al., 2009). Although, Otx2 is expressed broadly among retinoblastoma samples, its potential role as an oncogene in this tumor type has not been experimentally assessed; the possibility that Otx2 is solely a cell lineage marker maintained in transformed retinal progenitor cells has yet to be excluded based on functional studies.
  
Entity Coloboma
Note Developmental defects of the eye.
Disease Coloboma, defined as a fissure in the ocular tissue (Onwochei et al., 2000). These result from incomplete closure of the fetal fissure (an invagination of the optic stalk and optic vesicle), whose function is to provide a scaffold for the formation of the optic cup and for the vessels responsible for retinal vascularization. Colobomata are predominately developmental defects that present at birth. Various genes, including OTX2, have been implicated in hereditary syndromes predisposing to coloboma (Omwochei et al., 2000; Wyatt et al., 2008), and sporadic cases have implicated teratogens, though evidence implicating particular agents is generally anecdotal (Omwochei et al., 2000).
Cytogenetics Germline OTX2 mutations have been identified in patients with bilateral eye defects including colobomata and anophthalmia (Wyatt et al., 2008).
  
Entity Anophthalmia and microphthalmia (absent or small eyes, respectively)
Note Developmental defects of the eye.
Disease Microphthalmia is clinically defined as an eye with an axial diameter measuring at least two standard deviations below the mean for the corresponding age group (Omwochei et al., 2000), whereas anophthalmia is diagnosed when no clinically apparent eye structure is present. Those affected generally harbor bilateral malformations. Like coloboma, some forms of anophthalmia/microphthalmia are clearly inheritable, while for other cases environmental factors have been implicated but not definitively so (Verma et al., 2007). Anophthalmia/microphthalmia can present as secondary malformations following colobomata.
Cytogenetics Various genes have been implicated, including SOX2 (autosomal dominant inheritance), OTX2 (autosomal dominant), CHX10 (autosomal recessive), and RAX (autosomal recessive; Verma et al., 2007; Wyatt et al., 2008).
  

External links

Nomenclature
HGNC (Hugo)OTX2   8522
Cards
AtlasOTX2ID46429ch14q22
Entrez_Gene (NCBI)OTX2  5015  orthodenticle homeobox 2
GeneCards (Weizmann)OTX2
Ensembl (Hinxton)ENSG00000165588 [Gene_View]  chr14:57267425-57277194 [Contig_View]  OTX2 [Vega]
ICGC DataPortalENSG00000165588
AceView (NCBI)OTX2
Genatlas (Paris)OTX2
WikiGenes5015
SOURCE (Princeton)NM_001270523 NM_001270524 NM_001270525 NM_021728 NM_172337
Genomic and cartography
GoldenPath (UCSC)OTX2  -  14q22.3   chr14:57267425-57277194 -  14q22.3   [Description]    (hg19-Feb_2009)
EnsemblOTX2 - 14q22.3 [CytoView]
Mapping of homologs : NCBIOTX2 [Mapview]
OMIM600037   610125   613986   
Gene and transcription
Genbank (Entrez)AB593056 AB593057 AB593058 AF093138 AK314271
RefSeq transcript (Entrez)NM_001270523 NM_001270524 NM_001270525 NM_021728 NM_172337
RefSeq genomic (Entrez)AC_000146 NC_000014 NC_018925 NG_008204 NT_026437 NW_001838111 NW_004929393
Consensus coding sequences : CCDS (NCBI)OTX2
Cluster EST : UnigeneHs.741558 [ NCBI ]
CGAP (NCI)Hs.741558
Alternative Splicing : Fast-db (Paris)GSHG0009391
Alternative Splicing GalleryENSG00000165588
Gene ExpressionOTX2 [ NCBI-GEO ]     OTX2 [ SEEK ]   OTX2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP32243 (Uniprot)
NextProtP32243  [Medical]
With graphics : InterProP32243
Splice isoforms : SwissVarP32243 (Swissvar)
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox_CS    Homeobox_dom    Homeodomain-like    Otx2_TF    Otx_TF    Otx_TF_C   
Related proteins : CluSTrP32243
Domain families : Pfam (Sanger)Homeobox (PF00046)    TF_Otx (PF03529)   
Domain families : Pfam (NCBI)pfam00046    pfam03529   
Domain families : Smart (EMBL)HOX (SM00389)  
DMDM Disease mutations5015
Blocks (Seattle)P32243
Human Protein AtlasENSG00000165588
Peptide AtlasP32243
HPRD07190
IPIIPI00027683   IPI00172654   IPI01025803   IPI01026243   IPI01026095   
Protein Interaction databases
DIP (DOE-UCLA)P32243
IntAct (EBI)P32243
FunCoupENSG00000165588
BioGRIDOTX2
IntegromeDBOTX2
STRING (EMBL)OTX2
Ontologies - Pathways
QuickGOP32243
Ontology : AmiGORNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  cell fate specification  protein binding  nucleus  cytoplasm  protein complex assembly  axon guidance  endoderm development  eukaryotic initiation factor 4E binding  regulation of smoothened signaling pathway  dorsal/ventral pattern formation  metencephalon development  growth cone  forebrain development  midbrain development  somite rostral/caudal axis specification  positive regulation of embryonic development  regulation of fibroblast growth factor receptor signaling pathway  inner ear morphogenesis  eye photoreceptor cell fate commitment  protein complex  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  diencephalon morphogenesis  primitive streak formation  positive regulation of gastrulation  
Ontology : EGO-EBIRNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  cell fate specification  protein binding  nucleus  cytoplasm  protein complex assembly  axon guidance  endoderm development  eukaryotic initiation factor 4E binding  regulation of smoothened signaling pathway  dorsal/ventral pattern formation  metencephalon development  growth cone  forebrain development  midbrain development  somite rostral/caudal axis specification  positive regulation of embryonic development  regulation of fibroblast growth factor receptor signaling pathway  inner ear morphogenesis  eye photoreceptor cell fate commitment  protein complex  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  diencephalon morphogenesis  primitive streak formation  positive regulation of gastrulation  
Protein Interaction DatabaseOTX2
Wikipedia pathwaysOTX2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)OTX2
SNP (GeneSNP Utah)OTX2
SNP : HGBaseOTX2
Genetic variants : HAPMAPOTX2
1000_GenomesOTX2 
ICGC programENSG00000165588 
CONAN: Copy Number AnalysisOTX2 
Somatic Mutations in Cancer : COSMICOTX2 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Eye diseases - LOVD
LOVD (Leiden Open Variation Database)MRC Human Genetics Unit LOVD at MRC IGMM
DECIPHER (Syndromes)14:57267425-57277194
Mutations and Diseases : HGMDOTX2
OMIM600037    610125    613986   
MedgenOTX2
GENETestsOTX2
Disease Genetic AssociationOTX2
Huge Navigator OTX2 [HugePedia]  OTX2 [HugeCancerGEM]
Genomic VariantsOTX2  OTX2 [DGVbeta]
Exome VariantOTX2
dbVarOTX2
ClinVarOTX2
snp3D : Map Gene to Disease5015
DGIdb (Curated mutations)OTX2
DGIdb (Drug Gene Interaction db)OTX2
General knowledge
Homologs : HomoloGeneOTX2
Homology/Alignments : Family Browser (UCSC)OTX2
Phylogenetic Trees/Animal Genes : TreeFamOTX2
Chemical/Protein Interactions : CTD5015
Chemical/Pharm GKB GenePA32849
Clinical trialOTX2
Cancer Resource (Charite)ENSG00000165588
Other databases
Probes
Litterature
PubMed67 Pubmed reference(s) in Entrez
CoreMineOTX2
GoPubMedOTX2
iHOPOTX2

Bibliography

Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum.
Frantz GD, Weimann JM, Levin ME, McConnell SK.
J Neurosci. 1994 Oct;14(10):5725-40.
PMID 7931541
 
Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation.
Acampora D, Mazan S, Lallemand Y, Avantaggiato V, Maury M, Simeone A, Brulet P.
Development. 1995 Oct;121(10):3279-90.
PMID 7588062
 
Mouse Otx2 functions in the formation and patterning of rostral head.
Matsuo I, Kuratani S, Kimura C, Takeda N, Aizawa S.
Genes Dev. 1995 Nov 1;9(21):2646-58.
PMID 7590242
 
The subcellular localization of Otx2 is cell-type specific and developmentally regulated in the mouse retina.
Baas D, Bumsted KM, Martinez JA, Vaccarino FM, Wikler KC, Barnstable CJ.
Brain Res Mol Brain Res. 2000 May 31;78(1-2):26-37.
PMID 10891582
 
Functional domains of the cone-rod homeobox (CRX) transcription factor.
Chau KY, Chen S, Zack DJ, Ono SJ.
J Biol Chem. 2000 Nov 24;275(47):37264-70.
PMID 10984472
 
Ocular colobomata.
Onwochei BC, Simon JW, Bateman JB, Couture KC, Mir E.
Surv Ophthalmol. 2000 Nov-Dec;45(3):175-94. (REVIEW)
PMID 11094243
 
An anatomy of normal and malignant gene expression.
Boon K, Osorio EC, Greenhut SF, Schaefer CF, Shoemaker J, Polyak K, Morin PJ, Buetow KH, Strausberg RL, De Souza SJ, Riggins GJ.
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11287-92. Epub 2002 Jul 15.
PMID 12119410
 
Heterozygous mutations of OTX2 cause severe ocular malformations.
Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM.
Am J Hum Genet. 2005 Jun;76(6):1008-22. Epub 2005 Apr 21.
PMID 15846561
 
Otx2 regulates subtype specification and neurogenesis in the midbrain.
Vernay B, Koch M, Vaccarino F, Briscoe J, Simeone A, Kageyama R, Ang SL.
J Neurosci. 2005 May 11;25(19):4856-67.
PMID 15888661
 
Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization.
Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P.
Genes Chromosomes Cancer. 2005 Jul;43(3):294-301.
PMID 15834944
 
Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants.
Chatelain G, Fossat N, Brun G, Lamonerie T.
J Mol Med. 2006 Jul;84(7):604-15. Epub 2006 Apr 11.
PMID 16607563
 
Temporal and spatial delineation of mouse Otx2 functions by conditional self-knockout.
Fossat N, Chatelain G, Brun G, Lamonerie T.
EMBO Rep. 2006 Aug;7(8):824-30. Epub 2006 Jul 14.
PMID 16845372
 
Anophthalmia and microphthalmia.
Verma AS, Fitzpatrick DR.
Orphanet J Rare Dis. 2007 Nov 26;2:47. (REVIEW)
PMID 18039390
 
A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency.
Diaczok D, Romero C, Zunich J, Marshall I, Radovick S.
J Clin Endocrinol Metab. 2008 Nov;93(11):4351-9. Epub 2008 Aug 26.
PMID 18728160
 
Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon.
Omodei D, Acampora D, Mancuso P, Prakash N, Di Giovannantonio LG, Wurst W, Simeone A.
Development. 2008 Oct;135(20):3459-70.
PMID 18820178
 
Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity.
Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK.
Cell. 2008 Aug 8;134(3):508-20.
PMID 18692473
 
Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma.
Wyatt A, Bakrania P, Bunyan DJ, Osborne RJ, Crolla JA, Salt A, Ayuso C, Newbury-Ecob R, Abou-Rayyah Y, Collin JR, Robinson D, Ragge N.
Hum Mutat. 2008 Nov;29(11):E278-83.
PMID 18781617
 
Differential CRX and OTX2 expression in human retina and retinoblastoma.
Glubrecht DD, Kim JH, Russell L, Bamforth JS, Godbout R.
J Neurochem. 2009 Oct;111(1):250-63. Epub 2009 Aug 3.
PMID 19686387
 
Expression of the homeobox genes PAX6, OTX2, and OTX1 in the early human fetal retina.
Larsen KB, Lutterodt M, Rath MF, Moller M.
Int J Dev Neurosci. 2009 Aug;27(5):485-92. Epub 2009 May 3.
PMID 19414065
 
CDD: specific functional annotation with the Conserved Domain Database.
Marchler-Bauer A, Anderson JB, Chitsaz F, Derbyshire MK, DeWeese-Scott C, Fong JH, Geer LY, Geer RC, Gonzales NR, Gwadz M, He S, Hurwitz DI, Jackson JD, Ke Z, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Tasneem A, Thanki N, Yamashita RA, Zhang D, Zhang N, Bryant SH.
Nucleic Acids Res. 2009 Jan;37(Database issue):D205-10. Epub 2008 Nov 4.
PMID 18984618
 
From brain formation to plasticity: insights on Otx2 homeoprotein.
Sugiyama S, Prochiantz A, Hensch TK.
Dev Growth Differ. 2009 Apr;51(3):369-77. Epub 2009 Feb 27. (REVIEW)
PMID 19298552
 
OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.
Adamson DC, Shi Q, Wortham M, Northcott PA, Di C, Duncan CG, Li J, McLendon RE, Bigner DD, Taylor MD, Yan H.
Cancer Res. 2010 Jan 1;70(1):181-91. Epub 2009 Dec 22.
PMID 20028867
 
Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain.
Larsen KB, Lutterodt MC, Mollgard K, Moller M.
J Histochem Cytochem. 2010 Jul;58(7):669-78. Epub 2010 Mar 30.
PMID 20354145
 
Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years.
Northcott PA, Rutka JT, Taylor MD.
Neurosurg Focus. 2010 Jan;28(1):E6. (REVIEW)
PMID 20043721
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written09-2010Matthew Wortham
Department of Pathology, Duke University Medical Center, DUMC-3156, 199B-MSRB, Research Drive, Durham, NC 27710, USA

Citation

This paper should be referenced as such :
Wortham, M
OTX2 (orthodenticle homeobox 2)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(5):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/OTX2ID46429ch14q22.html

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indexed on : Thu Dec 4 15:25:17 CET 2014

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