OTX2 (orthodenticle homeobox 2)

2010-09-01   Matthew Wortham 

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





Total gene sequence: 9757 bp.


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.


OTX2P1 located at 9q21.



Isoforms a and b share the same coding exons, therefore both isoforms encode full-length (289 amino acid) Otx2 protein.
Atlas Image
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).


289 amino acids, see diagram for domain organization.


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).


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).


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).


Shares sequence homology and general domain organization with OTX family members Otx1 and Crx.



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.


None detected in medulloblastoma.

Implicated in

Entity name
Pediatric CNS cancer (medulloblastoma)
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).
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).
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 name
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).
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 name
Developmental defects of the eye.
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).
Germline OTX2 mutations have been identified in patients with bilateral eye defects including colobomata and anophthalmia (Wyatt et al., 2008).
Entity name
Anophthalmia and microphthalmia (absent or small eyes, respectively)
Developmental defects of the eye.
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.
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).


Pubmed IDLast YearTitleAuthors
75880621995Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation.Acampora D et al
200288672010OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.Adamson DC et al
108915822000The subcellular localization of Otx2 is cell-type specific and developmentally regulated in the mouse retina.Baas D et al
121194102002An anatomy of normal and malignant gene expression.Boon K et al
166075632006Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants.Chatelain G et al
109844722000Functional domains of the cone-rod homeobox (CRX) transcription factor.Chau KY et al
187281602008A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency.Diaczok D et al
168453722006Temporal and spatial delineation of mouse Otx2 functions by conditional self-knockout.Fossat N et al
79315411994Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum.Frantz GD et al
196863872009Differential CRX and OTX2 expression in human retina and retinoblastoma.Glubrecht DD et al
203541452010Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain.Larsen KB et al
189846182009CDD: specific functional annotation with the Conserved Domain Database.Marchler-Bauer A et al
75902421995Mouse Otx2 functions in the formation and patterning of rostral head.Matsuo I et al
200437212010Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years.Northcott PA et al
188201782008Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon.Omodei D et al
110942432000Ocular colobomata.Onwochei BC et al
158465612005Heterozygous mutations of OTX2 cause severe ocular malformations.Ragge NK et al
192985522009From brain formation to plasticity: insights on Otx2 homeoprotein.Sugiyama S et al
180393902007Anophthalmia and microphthalmia.Verma AS et al
158886612005Otx2 regulates subtype specification and neurogenesis in the midbrain.Vernay B et al
187816172008Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma.Wyatt A et al
158349442005Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization.Zielinski B et al

Other Information

Locus ID:

NCBI: 5015
MIM: 600037
HGNC: 8522
Ensembl: ENSG00000165588


dbSNP: 5015
ClinVar: 5015
TCGA: ENSG00000165588


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
158465612005Heterozygous mutations of OTX2 cause severe ocular malformations.94
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
157058912005Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.55
167126952006Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.51
210575062010Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP.49
200288672010OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.48
187816172008Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma.36
219648302012OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells.34
179054802009The transcription factor PITX3 is associated with sporadic Parkinson's disease.31
157058632005Genomic amplification of orthodenticle homologue 2 in medulloblastomas.30


Matthew Wortham

OTX2 (orthodenticle homeobox 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-09-01

Online version: http://atlasgeneticsoncology.org/gene/46429/otx2