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  6. Homeobox protein OTX2

Tbio Homeobox protein OTX2

Probably plays a role in the development of the brain and the sense organs. Can bind to the BCD target sequence (BTS): 5'-TCTAATCCC-3'.

This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

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Property Summary

NCBI Gene PubMed Count 75
PubMed Score 297.61
PubTator Score 130.88

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (7)

Disease Target Count Z-score Confidence
Coloboma 52 3.819 1.9
Panhypopituitarism 11 0.0 5.0
Disease Target Count Z-score Confidence
Microphthalmia 79 5.41 2.7

Expression

  Differential Expression (5)

Disease log2 FC p
group 4 medulloblastoma 7.800 6.6e-08
atypical teratoid / rhabdoid tumor 4.900 2.8e-03
medulloblastoma, large-cell 7.700 9.1e-05
chronic rhinosinusitis 1.106 2.6e-02
cystic fibrosis and chronic rhinosinusit... 2.277 9.2e-03

Synonym

Accession P32243 B2RAN5 Q6GTV3 Q9HAW3 Q9P2R1
Symbols CPHD6
MCOPS5

Gene

OTX2

PANTHER Protein Class (3)

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG

 UniProt Keyword (9)

 GO Function (3)

 GO Component (3)

 GO Process (12)

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 Compartment GO Term (21)

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 OMIM Phenotype (3)

 MGI Phenotype (20)

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 HCA RNA Cell Line (16)

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Pathway (4)

Gene RIF (58)

PMID Text
26554466 demonstrated the role of OTX2 on TAp63 regulation necessary for the correct formation of macular neuroepithelium
26398939 A novel role for OTX2 in self-renewal and migration of human embryonic neural precursors and Medulloblastoma cells, is reported.
26397460 Loss of OTX2 expression resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation
25589041 Agnathia-otocephaly complex and asymmetric velopharyngeal insufficiency due to an in-frame duplication in OTX2.
25571874 This epigenome-wide DNA methylation analysis in postmortem hippocampus and prefrontal cortex specimens confirmed OTX2 DNA methylation profiles in major depression
25542770 SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia
25351180 We showed that miR-410 directly regulates predicted target genes OTX2 and RPE65.
25293953 OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium.
25198066 OTX2 overexpression is associated with medulloblastoma.
24816892 a role for OTX2 dosage sensitivity in human craniofacial development
24580054 Endogenous OTX2 from a medulloblastoma cell line is O-GlcNAcylated at several sites.
24227910 VEGF-A, Otx2 homeobox and p53 family genes are expressed in proliferative vitreoretinopathy
23794319 OTX2 gene duplication is associated with autosomal dominant oculoauriculovertebral syndrome.
23566845 Otx2c is a novel alternative splicing variant of Otx2 gene and it is tightly regulated during the differentiation process demonstrating that it may have a potential role in embryonic stem cell maintenance and differentiation.
23179372 This study showed that OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels.
22986744 OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma.
22783640 There is no genotype-phenotype correlation and the severity of the disease varies not only by the specific OTX2 mutations but also among individuals harboring the same mutation, suggesting the involvement of multiple levels of regulation.
22715480 A novel missense heterozygous OTX2 mutation acts as a dominant negative inhibitor of target gene expression in a patient with combined pituitary hormone deficiency (CPHD), pituitary malformation, and optic nerve hypoplasia.
22577225 This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation.
22508046 MiR-206 regulates Otx2 expression in glioma and neuroblastoma cell lines.
22268617 We have identified a novel mutation of the OTX2 gene in a Han Chinese family featuring various anophthalmia and microphthalmia phenotypes.
22259223 these findings emphasize the role of OTX2 in regulating the human TYR gene, with implications for inter-individual differences in melanin synthesis, retinal development, and function as well as susceptibility to retinal degeneration associated with aging.
22204637 The OTX2 mutation in c.313C > T causing p.Gln105X and a premature stop codon is consistent with the loss of function mutations observed in A/M patients.
22198066 Mutation analysis was performed after sequencing the entire coding regions of OTX2 and PRRX1 genes isolated from the proband and his parents. After thorough analysis, no DNA variations were detected
22016811 functional interaction between OTX2 and MYC in regulating gene expression in medulloblastoma
21964830 silencing of OTX2 inhibited cell proliferation and resulted in a neuronal-like differentiation; downregulated genes were enriched for cycle and visual perception genes; upregulated genes were enriched for genes involved development and differentiation
21353197 This high frequency of causal submicroscopic chromosomal aberrations in patients with congenital ocular malformation warrants implementation of array comparative genomic hybridization in the diagnostic work-up of these patients.
21057506 Otx2 is required to specify neuron subtype in ventral tegmental area and confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) poisoning.
21047732 OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.
20628086 Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
20573704 OTX2 overexpression protects dopaminergic neurons in ventral mesencephalic cultures from Parkinson's disease-relevant toxin, 1-methyl-4-phenylpyridinium, whereas OTX2 downregulation using short hairpin RNA increases their susceptibility.
20530484 SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
20494911 Observational study of gene-disease association. (HuGE Navigator)
20486942 Four of the five OTX2-positive anophthalmia/microphthalmia patients in our study displayed additional systemic findings, including two novel features, Wolf-Parkinson-White syndrome and an anteriorly placed anus
20396904 A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency.
20354145 The early expression of OTX2 in proliferative cell layers of the human fetal brain supports the concept that this homeobox gene is important in neuronal cell development and differentiation.
20057906 Observational study of gene-disease association. (HuGE Navigator)
20028867 Our findings define OTX2 as an important oncogenic driver in medulloblastoma.
19965921 OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations, and that OTX2 can transactivate GNRH1 as well as HESX1 and POU1F1.
19956411 Mutations in OTX2 have been reported in association with major developmental malformations of the eye, with retinal dystrophies and with pituitary dysfunction and seizure activity in some cases.
19913121 Observational study of gene-disease association. (HuGE Navigator)
19686387 OTX2 expression in the inner nuclear layer of the retina.
19414065 In the human fetal eye, OTX2 was localized to the nuclei of retinal pigment epithelium. Expression peaked around fetal days 48-54.
18854396 OTX2 mutation is a cause of combined pituitary hormone deficiency (CPHD).
18849347 OTR1, OTX2 and CRX act as positive modulators of the BEST1 promoter in the retinal pigment epithelium.
18781617 Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma are reported.
18728160 A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression in combined pituittary hormone deficiency.
18666230 BOR and OAVS features are associated with duplication of SIX1, SIX6 and OTX2 resulting from a complex chromosomal rearrangement.
17905480 Observational study of gene-disease association. (HuGE Navigator)
17541950 Observational study of gene-disease association. (HuGE Navigator)
17541950 Polymorphisms in the homeobox gene OTX2 is associated with bipolar disorder
17060451 Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors
16712695 This review describes how cross regulation for PAX6, SOX2 and perhaps OTX2 has now been uncovered, pointing to the mechanisms that can fine-tune the expression of three such essential components in eye development.
16607563 Molecular diagnostic of human mutant OTX2 proteins discriminates hypomorphic and loss of function mutations from other mutations that may not be relevant to ocular pathology
15846561 Heterozygous mutations of OTX2 cause severe ocular malformations.
15705891 Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features.
15705863 OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene.
12559959 Data suggest that OTX2 may regulate retinal pigment epithelium (RPE)-specific target genes, such as DOPAchrome tautomerase (DCT), thereby maintaining the homeostasis of RPE.

AA Sequence 

MMSYLKQPPYAVNGLSLTTSGMDLLHPSVGYPATPRKQRRERTTFTRAQLDVLEALFAKTRYPDIFMREE      1 - 70
VALKINLPESRVQVWFKNRRAKCRQQQQQQQNGGQNKVRPAKKKTSPAREVSSESGTSGQFTPPSSTSVP     71 - 140
TIASSSAPVSIWSPASISPLSDPLSTSSSCMQRSYPMTYTQASGYSQGYAGSTSYFGGMDCGSYLTPMHH    141 - 210
QLPGPGATLSPMGTNAVTSHLNQSPASLSTQGYGASSLGFNSTTDCLDYKDQTASWKLNFNADCLDYKDQ    211 - 280
TSSWKFQVL                                                                 281 - 289
//

Text Mined References (76)

PMID Year Title
26554466 2015 OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.
26398939 2015 OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells.
26397460 2015 OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways.
25589041 2015 Agnathia-otocephaly complex and asymmetric velopharyngeal insufficiency due to an in-frame duplication in OTX2.
25571874 2015 Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression.
25542770 2015 SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia.
25351180 2015 miR-410 Inhibition Induces RPE Differentiation of Amniotic Epithelial Stem Cells via Overexpression of OTX2 and RPE65.
25293953 2014 OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium.
25198066 2014 Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.
24816892 2014 OTX2 duplication is implicated in hemifacial microsomia.
24580054 2014 Microarray discovery of new OGT substrates: the medulloblastoma oncogene OTX2 is O-GlcNAcylated.
24431302 2014 Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease.
24399192 2014 Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons.
24227910 2013 Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy.
24167467 2013 Otocephaly-Dysgnathia Complex: Description of Four Cases and Confirmation of the Role of OTX2.
23794319 2013 Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication.
23566845 2013 Specific expression pattern of a novel Otx2 splicing variant during neural differentiation.
23179372 2013 OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels.
22986744 2012 OTX2 represses myogenic and neuronal differentiation in medulloblastoma cells.
22783640 2011 Brain development is a multi-level regulated process--the case of the OTX2 gene.
22715480 2012 A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve.
22577225 2012 OTX2 mutations contribute to the otocephaly-dysgnathia complex.
22508046 2012 MiR-206 regulates neural cells proliferation and apoptosis via Otx2.
22268617 2012 Novel OTX2 mutation associated with congenital anophthalmia and microphthalmia in a Han Chinese family.
22259223 2012 Regulation of the human tyrosinase gene in retinal pigment epithelium cells: the significance of transcription factor orthodenticle homeobox 2 and its polymorphic binding site.
22204637 2011 Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations.
22198066 2012 Agnathia-otocephaly complex: a case report and examination of the OTX2 and PRRX1 genes.
22016811 2011 Joint binding of OTX2 and MYC in promotor regions is associated with high gene expression in medulloblastoma.
21964830 2012 OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells.
21697133 2011 Full-length transcriptome analysis of human retina-derived cell lines ARPE-19 and Y79 using the vector-capping method.
21353197 2011 High frequency of submicroscopic chromosomal deletions in patients with idiopathic congenital eye malformations.
21057506 2010 Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP.
21047732 2010 Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines.
20628086 2010 Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
20573704 2010 The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons.
20530484 2010 SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
20494911 2010 Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases.
20486942 2011 OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype.
20396904 2010 A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency.
20354145 2010 Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain.
20057906 2009 Mutational screening of 10 genes in Chinese patients with microphthalmia and/or coloboma.
20028867 2010 OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.
19965921 2010 Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype.
19956411 2009 A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction.
19951692 2009 Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.
19913121 2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
19686387 2009 Differential CRX and OTX2 expression in human retina and retinoblastoma.
19414065 2009 Expression of the homeobox genes PAX6, OTX2, and OTX1 in the early human fetal retina.
18854396 2009 OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary.
18849347 2009 BEST1 expression in the retinal pigment epithelium is modulated by OTX family members.
18781617 2008 Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma.
18728160 2008 A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency.
18666230 2008 Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement.
17905480 2009 The transcription factor PITX3 is associated with sporadic Parkinson's disease.
17541950 2007 Polymorphisms in the homeobox gene OTX2 may be a risk factor for bipolar disorder.
17060451 2007 Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors.
16713569 2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.
16712695 2006 Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.
16607563 2006 Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants.
16344560 2006 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.
16267555 2005 The transcription factor Engrailed-2 guides retinal axons.
15846561 2005 Heterozygous mutations of OTX2 cause severe ocular malformations.
15705891 2005 Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.
15705863 2005 Genomic amplification of orthodenticle homologue 2 in medulloblastomas.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15105370 2004 Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain.
14702039 2004 Complete sequencing and characterization of 21,243 full-length human cDNAs.
12663655 2003 OTX2 activates the molecular network underlying retina pigment epithelium differentiation.
12559959 2003 OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
10623575 2000 OTX2 directly interacts with LIM1 and HNF-3beta.
10372988 1999 Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells.
10354480 1999 OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression.
9520436 1998 Developmental rescue of Drosophila cephalic defects by the human Otx genes.
8101484 1993 A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo.
7959790 1994 Chromosome locations of human EMX and OTX genes.