OTX2

Summary

OTX2 (orthodenticle homeobox 2, HGNC:8522) is a protein-coding gene on chromosome 14q22.3, encoding Homeobox protein OTX2 (P32243). Transcription factor probably involved in the development of the brain and the sense organs. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 5015 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic microphthalmia type 5 (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 311 total — 49 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 102
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 45 downstream targets (CollecTRI)
• MANE Select transcript: NM_021728

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8522
Approved symbol	OTX2
Name	orthodenticle homeobox 2
Location	14q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165588
Ensembl biotype	protein_coding
OMIM	600037
Entrez	5015

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000339475, ENST00000408990, ENST00000554559, ENST00000554788, ENST00000554845, ENST00000555006, ENST00000555804, ENST00000672125, ENST00000672264, ENST00000673035, ENST00000673481, ENST00000685244, ENST00000903453, ENST00000939197, ENST00000939198, ENST00000939199, ENST00000939200, ENST00000939201

RefSeq mRNA: 5 — MANE Select: NM_021728 NM_001270523, NM_001270524, NM_001270525, NM_021728, NM_172337

CCDS: CCDS41960, CCDS9728

Canonical transcript exons

ENST00000672264 — 5 exons

Exon	Start	End
ENSE00001094441	56804188	56804363
ENSE00001250675	56810159	56810222
ENSE00001390987	56805360	56805575
ENSE00003899741	56799905	56802355
ENSE00003901429	56810376	56810479

Expression profiles

Bgee: expression breadth broad, 62 present calls, max score 99.75.

FANTOM5 (CAGE): breadth broad, TPM avg 18.4785 / max 1782.5033, expressed in 297 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143394	10.4209	274
143387	6.5347	214
143392	1.0694	167
143393	0.2953	78
143386	0.1245	40
143397	0.0337	9

Top tissues by expression

241 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.75	gold quality
oocyte	CL:0000023	99.74	gold quality
pigmented layer of retina	UBERON:0001782	99.38	gold quality
cerebellar hemisphere	UBERON:0002245	82.97	gold quality
cerebellar cortex	UBERON:0002129	82.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.66	gold quality
cerebellum	UBERON:0002037	81.43	gold quality
lateral nuclear group of thalamus	UBERON:0002736	79.02	gold quality
nasal cavity epithelium	UBERON:0005384	77.00	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.81	gold quality
tibialis anterior	UBERON:0001385	68.63	silver quality
substantia nigra	UBERON:0002038	66.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.60	gold quality
midbrain	UBERON:0001891	65.41	gold quality
nasal cavity mucosa	UBERON:0001826	64.61	gold quality
hypothalamus	UBERON:0001898	63.98	gold quality
ventral tegmental area	UBERON:0002691	63.71	gold quality
dorsal plus ventral thalamus	UBERON:0001897	61.16	gold quality
pancreatic ductal cell	CL:0002079	59.18	silver quality
cerebellar vermis	UBERON:0004720	58.15	silver quality
deltoid	UBERON:0001476	57.66	silver quality
ileal mucosa	UBERON:0000331	57.58	silver quality
ventricular zone	UBERON:0003053	56.60	gold quality
epithelial cell of pancreas	CL:0000083	54.55	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
adenohypophysis	UBERON:0002196	52.86	gold quality
sural nerve	UBERON:0015488	50.45	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	571.71
E-GEOD-75140	yes	532.38
E-GEOD-135922	yes	279.70
E-GEOD-93593	yes	15.42
E-GEOD-109979	no	581.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

45 targets.

Target	Regulation
ASMT
AURKA	Activation
BEST1	Activation
CCNG2	Activation
CDC25C	Activation
CRX	Unknown
DCT	Unknown
DKK1
FGF8	Unknown
GDF7
GNRH1	Activation
GNRHR
GRB10
GSC	Activation
HESX1	Unknown
HHEX
IGF1	Activation
IL6	Activation
LDB1
LEFTY1
ME3
MITF	Unknown
MSX1	Unknown
NCAM1
NEUROG2	Unknown
NPPA
NRL
OTX2
PAX6	Activation
POU1F1	Unknown

JASPAR motifs

Motif	Name	Family
MA0712.1	OTX2	Paired-related HD factors
MA0712.2	OTX2	Paired-related HD factors
MA0712.3	OTX2	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): CTNNB1, ESRRB, FEZF1, GBX2, HOXB1, HOXB2, HOXB3, NEUROD1, NR2E3, OTX2, PAX6, RARA, YY1

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that OTX2 may regulate retinal pigment epithelium (RPE)-specific target genes, such as DOPAchrome tautomerase (DCT), thereby maintaining the homeostasis of RPE. (PMID:12559959)
• 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. (PMID:15705863)
• Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. (PMID:15705891)
• Heterozygous mutations of OTX2 cause severe ocular malformations. (PMID:15846561)
• 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 (PMID:16607563)
• 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. (PMID:16712695)
• Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors (PMID:17060451)
• Polymorphisms in the homeobox gene OTX2 is associated with bipolar disorder (PMID:17541950)
• BOR and OAVS features are associated with duplication of SIX1, SIX6 and OTX2 resulting from a complex chromosomal rearrangement. (PMID:18666230)
• 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. (PMID:18728160)
• Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma are reported. (PMID:18781617)
• OTR1, OTX2 and CRX act as positive modulators of the BEST1 promoter in the retinal pigment epithelium. (PMID:18849347)
• OTX2 mutation is a cause of combined pituitary hormone deficiency (CPHD). (PMID:18854396)
• In the human fetal eye, OTX2 was localized to the nuclei of retinal pigment epithelium. Expression peaked around fetal days 48-54. (PMID:19414065)
• OTX2 expression in the inner nuclear layer of the retina. (PMID:19686387)
• 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. (PMID:19956411)
• 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. (PMID:19965921)
• Our findings define OTX2 as an important oncogenic driver in medulloblastoma. (PMID:20028867)
• 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. (PMID:20354145)
• A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. (PMID:20396904)
• 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 (PMID:20486942)
• SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium. (PMID:20530484)
• 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. (PMID:20573704)
• OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle. (PMID:21047732)
• 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. (PMID:21057506)
• 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. (PMID:21353197)
• 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 (PMID:21964830)
• functional interaction between OTX2 and MYC in regulating gene expression in medulloblastoma (PMID:22016811)
• 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 (PMID:22198066)
• 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. (PMID:22204637)
• 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. (PMID:22259223)
• We have identified a novel mutation of the OTX2 gene in a Han Chinese family featuring various anophthalmia and microphthalmia phenotypes. (PMID:22268617)
• MiR-206 regulates Otx2 expression in glioma and neuroblastoma cell lines. (PMID:22508046)
• 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. (PMID:22577225)
• 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. (PMID:22715480)
• 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. (PMID:22783640)
• OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. (PMID:22986744)
• This study showed that OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. (PMID:23179372)
• 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. (PMID:23566845)
• OTX2 gene duplication is associated with autosomal dominant oculoauriculovertebral syndrome. (PMID:23794319)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	otx2b	ENSDARG00000011235
mus_musculus	Otx2	ENSMUSG00000021848
rattus_norvegicus	Otx2	ENSRNOG00000065063

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox protein OTX2 — P32243 (reviewed: P32243)

Alternative names: Orthodenticle homolog 2

All UniProt accessions (6): A0A5F9ZHY1, P32243, F1T0C9, F1T0D1, G3V3J3, G3V3P9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor probably involved in the development of the brain and the sense organs. Can bind to the bicoid/BCD target sequence (BTS): 5’-TCTAATCCC-3'.

Subcellular location. Nucleus.

Disease relevance. Microphthalmia, syndromic, 5 (MCOPS5) [MIM:610125] Patients manifest unilateral or bilateral microphthalmia/clinical anophthalmia and variable additional features including pituitary dysfunction, coloboma, microcornea, cataract, retinal dystrophy, hypoplasia or agenesis of the optic nerve, agenesis of the corpus callosum, developmental delay, joint laxity, hypotonia, and seizures. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. The disease is caused by variants affecting the gene represented in this entry. Pituitary hormone deficiency, combined, 6 (CPHD6) [MIM:613986] Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD6 patients manifest neonatal hypoglycemia, and deficiencies of growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. The disease is caused by variants affecting the gene represented in this entry. Retinal dystrophy, early-onset, with or without pituitary dysfunction (RDEOP) [MIM:610125] An autosomal dominant ocular disease characterized by pattern dystrophy of the retinal pigment epithelium, and photoreceptor degeneration. Mild developmental anomalies include optic nerve head dysplasia, microcornea, and Rathke’s cleft cyst. Some patients manifest pituitary dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family. Bicoid subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P32243-1	1	yes
P32243-2	2

RefSeq proteins (5): NP_001257452, NP_001257453, NP_001257454, NP_068374, NP_758840 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003022	Otx2_TF	Family
IPR003025	Otx_TF	Family
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013851	Otx_TF_C	Domain
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF00046, PF03529

UniProt features (14 total): sequence variant 7, compositionally biased region 3, chain 1, DNA-binding region 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32243-F1	60.99	0.22

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9823739	Formation of the anterior neural plate
R-HSA-9832991	Formation of the posterior neural plate

MSigDB gene sets: 475 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, HNF3ALPHA_Q6, TGCGCANK_UNKNOWN, SASAI_TARGETS_OF_CXCR6_AND_PTCH1_UP, SP3_Q3, GOBP_PRIMITIVE_STREAK_FORMATION, AACYNNNNTTCCS_UNKNOWN, GOBP_NEUROGENESIS, FOXO4_01, LHX3_01, CHX10_01, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN

GO Biological Process (15): regulation of transcription by RNA polymerase II (GO:0006357), axon guidance (GO:0007411), regulation of smoothened signaling pathway (GO:0008589), forebrain development (GO:0030900), midbrain development (GO:0030901), positive regulation of embryonic development (GO:0040019), regulation of fibroblast growth factor receptor signaling pathway (GO:0040036), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), protein-containing complex assembly (GO:0065003), dopaminergic neuron differentiation (GO:0071542), primitive streak formation (GO:0090009), positive regulation of gastrulation (GO:2000543), regulation of DNA-templated transcription (GO:0006355), multicellular organism development (GO:0007275)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), eukaryotic initiation factor 4E binding (GO:0008190), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), growth cone (GO:0030426), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gastrulation	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
anatomical structure development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of signal transduction	2
brain development	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
axonogenesis	1
neuron projection guidance	1
smoothened signaling pathway	1
embryo development	1
regulation of embryonic development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
fibroblast growth factor receptor signaling pathway	1
regulation of cellular response to growth factor stimulus	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cellular component assembly	1
protein-containing complex organization	1
neuron differentiation	1
gastrulation with mouth forming second	1
anterior/posterior axis specification	1
anatomical structure formation involved in morphogenesis	1
gastrulation	1
regulation of gastrulation	1
positive regulation of embryonic development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organismal process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
translation initiation factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1

Protein interactions and networks

STRING

2300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTX2	SOX2	P48431	897
OTX2	SIX6	O95475	881
OTX2	POU5F1	P31359	869
OTX2	SIX3	O95343	866
OTX2	FOXA2	Q9Y261	837
OTX2	PAX2	Q02962	819
OTX2	RCVRN	P35243	805
OTX2	FGF8	P55075	802
OTX2	SOX1	O00570	786
OTX2	FOXG1	P55315	774
OTX2	SOX3	P35714	765
OTX2	WNT1	P04628	749
OTX2	SHH	Q15465	740
OTX2	LMX1A	Q8TE12	736
OTX2	NR2E3	Q9Y5X4	735

IntAct

9 interactions, top by confidence:

A	B	Type	Score
OTX2	ATXN1	psi-mi:“MI:0915”(physical association)	0.550
OTX2	HBZ	psi-mi:“MI:0915”(physical association)	0.490
OTX2	CDK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
OTX2	SMARCB1	psi-mi:“MI:0915”(physical association)	0.370
OTX2	rep	psi-mi:“MI:0915”(physical association)	0.370
OTX2	GTF2F2	psi-mi:“MI:0914”(association)	0.350
ATXN1	OTX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (59): OTX2 (Two-hybrid), OTX2 (Reconstituted Complex), OTX2 (Affinity Capture-MS), OTX2 (Affinity Capture-MS), OTX2 (Affinity Capture-MS), OTX2 (Two-hybrid), FOXA2 (Reconstituted Complex), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid), OTX2 (Two-hybrid)

ESM2 similar proteins: A0PJS5, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A3KNJ3, A7Y7W3, A8K830, F6W2R2, F8VPY8, O15353, O42506, O43186, O54751, P14653, P17919, P28322, P31276, P32243, P40646, P43268, P57082, P70056, P80206, P83758, Q00288, Q06710, Q08820, Q16633, Q1KL10, Q28GC4, Q28IU6, Q2KJA4, Q4G112, Q503Z8, Q64693, Q66IK1, Q66IT9, Q7T1C0

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
LHX1	“up-regulates activity”	OTX2	binding
FOXA2	“down-regulates activity”	OTX2	binding
OTX2	“up-regulates quantity by expression”	RBP3	“transcriptional regulation”
HOXB1	“up-regulates quantity by expression”	OTX2	“transcriptional regulation”
HOXB2	“up-regulates quantity by expression”	OTX2	“transcriptional regulation”
HOXB3	“up-regulates quantity by expression”	OTX2	“transcriptional regulation”
SOX9	“up-regulates activity”	OTX2	binding
OTX2	“up-regulates quantity by expression”	BEST1	“transcriptional regulation”
SOX2/POU5F1	“up-regulates quantity by expression”	OTX2	“transcriptional regulation”
SOX17/POU5F1	“up-regulates quantity by expression”	OTX2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

311 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	17
Uncertain significance	160
Likely benign	61
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074471	NM_021728.4(OTX2):c.130del (p.Arg44fs)	Pathogenic
1184455	NM_021728.4(OTX2):c.634_640del (p.Tyr212fs)	Pathogenic
1213868	NM_021728.4(OTX2):c.698del (p.Asn233fs)	Pathogenic
1254572	NM_021728.4(OTX2):c.130dup (p.Arg44fs)	Pathogenic
1320211	NM_021728.4(OTX2):c.728dup (p.Ala244fs)	Pathogenic
1341157	GRCh37/hg19 14q22.3(chr14:57126229-57336190)x1	Pathogenic
1430222	NM_021728.4(OTX2):c.444dup (p.Thr149fs)	Pathogenic
1456134	NM_021728.4(OTX2):c.546_553del (p.Tyr183fs)	Pathogenic
1460253	NC_000014.8:g.(?57268453)(57272174_?)del	Pathogenic
1710330	NM_021728.4(OTX2):c.549T>G (p.Tyr183Ter)	Pathogenic
1710331	NM_021728.4(OTX2):c.588_591dup (p.Ala198fs)	Pathogenic
190249	NM_021728.4(OTX2):c.316del (p.Gln106fs)	Pathogenic
190250	NM_021728.4(OTX2):c.289C>T (p.Arg97Ter)	Pathogenic
2017389	NM_021728.4(OTX2):c.721C>T (p.Gln241Ter)	Pathogenic
2017904	NM_021728.4(OTX2):c.479G>A (p.Trp160Ter)	Pathogenic
2106827	NM_021728.4(OTX2):c.150del (p.Thr51fs)	Pathogenic
2112894	NM_021728.4(OTX2):c.565C>T (p.Gln189Ter)	Pathogenic
2124422	NM_021728.4(OTX2):c.316C>T (p.Gln106Ter)	Pathogenic
2427492	NC_000014.8:g.(?57268453)(57272174_?)dup	Pathogenic
2427493	NC_000014.8:g.(?57270959)(57274875_?)del	Pathogenic
2444436	NM_021728.4(OTX2):c.591T>G (p.Tyr197Ter)	Pathogenic
2628344	NM_021728.4(OTX2):c.471_474dup (p.Ile159fs)	Pathogenic
2715346	NM_021728.4(OTX2):c.190_191del (p.Leu64fs)	Pathogenic
280496	NM_021728.4(OTX2):c.226C>T (p.Arg76Ter)	Pathogenic
2812075	NM_021728.4(OTX2):c.655C>T (p.Gln219Ter)	Pathogenic
2833988	NM_021728.4(OTX2):c.363del (p.Lys122fs)	Pathogenic
2834678	NM_021728.4(OTX2):c.516del (p.Leu172fs)	Pathogenic
288042	NM_021728.4(OTX2):c.534C>A (p.Cys178Ter)	Pathogenic
30024	NM_021728.4(OTX2):c.428_429dup (p.Ser144fs)	Pathogenic
30025	NM_021728.4(OTX2):c.437C>G (p.Ser146Ter)	Pathogenic

SpliceAI

435 predictions. Top by Δscore:

Variant	Effect	Δscore
14:56802351:CATAC:C	acceptor_gain	1.0000
14:56802354:ACC:A	acceptor_loss	1.0000
14:56802355:CCT:C	acceptor_gain	1.0000
14:56802356:CTTGG:C	acceptor_loss	1.0000
14:56802357:T:C	acceptor_gain	1.0000
14:56802357:T:TC	acceptor_gain	1.0000
14:56804187:CC:C	donor_loss	1.0000
14:56804228:T:TA	donor_gain	1.0000
14:56804340:C:CC	acceptor_gain	1.0000
14:56805356:TTA:T	donor_loss	1.0000
14:56805357:TA:T	donor_loss	1.0000
14:56805358:A:AC	donor_gain	1.0000
14:56805358:A:AT	donor_loss	1.0000
14:56805358:AC:A	donor_gain	1.0000
14:56805359:C:CC	donor_gain	1.0000
14:56805359:CC:C	donor_gain	1.0000
14:56802352:ATAC:A	acceptor_gain	0.9900
14:56802353:TAC:T	acceptor_gain	0.9900
14:56802354:ACCTT:A	acceptor_gain	0.9900
14:56802356:C:CC	acceptor_gain	0.9900
14:56802356:C:T	acceptor_gain	0.9900
14:56804187:CCT:C	donor_gain	0.9900
14:56804189:TGC:T	donor_gain	0.9900
14:56804223:C:CT	donor_gain	0.9900
14:56804224:C:CT	donor_gain	0.9900
14:56804335:GGTGG:G	acceptor_gain	0.9900
14:56804336:GTGG:G	acceptor_gain	0.9900
14:56804337:TGG:T	acceptor_gain	0.9900
14:56804338:GG:G	acceptor_gain	0.9900
14:56804341:T:A	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000151894 (14:56806390 C>T), RS1000175646 (14:56800807 AACG>A), RS1000379009 (14:56807701 A>C,G,T), RS1000753999 (14:56804878 C>T), RS1000882 (14:56811525 A>G), RS1001413050 (14:56806810 C>A), RS1001680789 (14:56799803 T>C), RS1001982382 (14:56810848 G>A,T), RS1002070594 (14:56804076 G>A,C,T), RS1002114900 (14:56810617 G>A), RS1002354870 (14:56810591 G>A,T), RS1003423734 (14:56803453 G>A), RS1003962982 (14:56811174 C>T), RS1004267219 (14:56805169 C>A,T), RS1004292143 (14:56810876 T>A,G)

Disease associations

OMIM: gene MIM:600037 | disease phenotypes: MIM:613986, MIM:610125, MIM:204000, MIM:607834

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic microphthalmia type 5	Definitive	Autosomal dominant
pituitary hormone deficiency, combined, 6	Strong	Autosomal dominant
agnathia-otocephaly complex	Strong	Autosomal dominant
isolated anophthalmia-microphthalmia syndrome	Supportive	Autosomal dominant
septooptic dysplasia	Supportive	Autosomal dominant
combined pituitary hormone deficiencies, genetic form	Supportive	Autosomal dominant
patterned macular dystrophy	Supportive	Autosomal dominant

Mondo (16): pituitary hormone deficiency, combined, 6 (MONDO:0013518), syndromic microphthalmia type 5 (MONDO:0012413), Leber congenital amaurosis (MONDO:0018998), congenital hypothyroidism (MONDO:0018612), optic atrophy (MONDO:0003608), intellectual disability (MONDO:0001071), pathologic nystagmus (MONDO:0004843), anxiety (MONDO:0011918), 46,XY partial gonadal dysgenesis (MONDO:0016674), inherited retinal dystrophy (MONDO:0019118), microcephaly (MONDO:0001149), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), septooptic dysplasia (MONDO:0008428), combined pituitary hormone deficiencies, genetic form (MONDO:0013099), patterned macular dystrophy (MONDO:0020381)

Orphanet (8): Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Syndromic microphthalmia type 5 (Orphanet:178364), Leber congenital amaurosis (Orphanet:65), Congenital hypothyroidism (Orphanet:442), 46,XY partial gonadal dysgenesis (Orphanet:251510), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

102 total (30 of 102 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000141	Amenorrhea
HP:0000160	Narrow mouth
HP:0000171	Microglossia
HP:0000175	Cleft palate
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000458	Anosmia
HP:0000478	Abnormality of the eye
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000556	Retinal dystrophy
HP:0000568	Microphthalmia
HP:0000589	Coloboma
HP:0000609	Optic nerve hypoplasia
HP:0000610	Abnormal choroid morphology
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000789	Infertility
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000839	Pituitary dwarfism

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST007328_78	Alcohol consumption (drinks per week)	8.000000e-09
GCST007576_118	Chronotype	4.000000e-11
GCST008179_24	Moderate-to-late spontaneous preterm birth	2.000000e-07
GCST008757_17	Alcohol consumption	2.000000e-12
GCST010002_152	Refractive error	6.000000e-11
GCST011656_4	Lung cancer	8.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0006917	spontaneous preterm birth

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500
C566441	Microphthalmia, Syndromic 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases reaction, increases expression	10
trichostatin A	decreases expression, affects cotreatment	4
Tretinoin	decreases expression, decreases reaction, increases reaction, affects reaction, affects expression (+1 more)	4
bisphenol A	affects cotreatment, decreases expression, decreases reaction, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, increases reaction, decreases reaction, affects reaction (+1 more)	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation	2
bisphenol F	decreases expression	1
LY2955303	decreases expression, decreases reaction, increases expression, affects cotreatment	1
methylmercuric chloride	decreases expression	1
ascorbate-2-phosphate	decreases expression, affects binding, affects cotreatment	1
arsenite	increases methylation	1
decamethrin	affects cotreatment, affects reaction, increases expression	1
sodium arsenite	affects methylation	1
LE 135	affects reaction, decreases expression, affects cotreatment, decreases reaction	1
Chir 98014	decreases expression	1
Chir 99021	affects binding, affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
4-(2-(5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl)ethen-1-yl)benzoic acid	affects cotreatment, decreases expression, decreases reaction	1
4-(5,6-dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido)benzoic acid	affects cotreatment, decreases expression, decreases reaction	1
XAV939	affects binding, affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression, increases reaction, decreases reaction, affects reaction	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases expression, increases reaction, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases expression, increases reaction, increases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Ethanol	decreases expression, affects cotreatment	1
Ascorbic Acid	affects binding, affects cotreatment, decreases expression	1
Hexachlorocyclohexane	decreases reaction, increases expression, affects cotreatment	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5B4	SEES3-1V human OTX2, clone1	Embryonic stem cell	Male
CVCL_A5B5	SEES3-1V human OTX2, clone2	Embryonic stem cell	Male
CVCL_A5B6	SEES3-1V human OTX2, clone3	Embryonic stem cell	Male
CVCL_B1ZN	Abcam HeLa OTX2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00174850	PHASE4	COMPLETED	Switching From an SSRI to Tiagabine(GABITRIL) in Order to Alleviate SSRI Induced Sexual Dysfunction
NCT00302107	PHASE4	COMPLETED	A Placebo-Controlled Study of Mirtazapine for PTSD
NCT00596414	PHASE4	COMPLETED	Sedation and Analgesia for Transjugular Liver Biopsy: A Randomized Double Blind Placebo Controlled Trial
NCT00623454	PHASE4	COMPLETED	Non Cardiac Chest Pain and Benign Palpitations
NCT00676364	PHASE4	COMPLETED	Randomized Control Trial of a Topical Anesthetic to Evaluate Pain and Anxiety During Venipuncture
NCT00762099	PHASE4	UNKNOWN	Perioperative Pregabalin Use, Rehabilitation, Pain Outcomes and Anxiety Following Hip Surgery
NCT00826111	PHASE4	COMPLETED	The Effects of Eszopiclone and Lexapro on Prefrontal Glutamate and GABA in Depression With Anxiety and Insomnia
NCT00928772	PHASE4	TERMINATED	Cranial Electro Therapy Stimulation in Reducing Perioperative Anxiety
NCT00951483	PHASE4	COMPLETED	Cardiovascular Biomarkers and Quetiapine in Depression and Anxiety Patients
NCT01081249	PHASE4	COMPLETED	Effects of Oxytocin on Behavior and Physiology in a Psychotherapy Setting
NCT01148186	PHASE4	TERMINATED	An Intervention Study to Reduce the Use and Impact of Potentially Inappropriate Medications Among Older Adults
NCT01155804	PHASE4	UNKNOWN	Assessment of the Effectiveness of a Program of Preparation to Pregnancy and Delivery
NCT01285284	PHASE4	UNKNOWN	Effect of Music Over the Tolerance to Colonoscopy.
NCT01309074	PHASE4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01411709	PHASE4	COMPLETED	A Study On The Effect Of Vitano® On Physiological And Psychological Responses To Psychological Stress
NCT01441843	PHASE4	COMPLETED	Resistance Under the Microscope
NCT01486615	PHASE4	COMPLETED	Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone
NCT01502644	PHASE4	COMPLETED	Opioid Treatment for Chronic Low Back Pain and the Impact of Mood Symptoms
NCT01533415	PHASE4	COMPLETED	Use of Alpha-Stim Cranial-electrotherapy Stimulation (CES) in the Treatment of Anxiety
NCT01549691	PHASE4	COMPLETED	Reassessment of Premedication in Surgery
NCT01775605	PHASE4	WITHDRAWN	Study of Use of Synera for Pain During Local Skin Infiltration With Lidocaine Before Epidural Placement
NCT01830881	PHASE4	COMPLETED	Evaluation of Oral Midazolam in First-trimester Surgical Abortions
NCT01866605	PHASE4	COMPLETED	A Study of Methods to Reduce Anxiety in Preoperative Elective Surgical Patients
NCT01993459	PHASE4	COMPLETED	The Effects of Midazolam on the Quality of Postoperative Recovery
NCT02028026	PHASE4	WITHDRAWN	The Effects of Vilazodone on Glutamate in the Anterior Cingulate Cortex in Anxious Unipolar Depressives
NCT02168439	PHASE4	COMPLETED	Intranasal Dexmedetomidine vs Intranasal Midazolam as Anxiolysis Prior to Pediatric Laceration Repair
NCT02177955	PHASE4	COMPLETED	Comparative Study of Hemodynamic Changes Caused by Diazepam and Midazolam During Third Molar Surgery
NCT02213302	PHASE4	COMPLETED	Premedication by Midazolam for Emergency Surgery
NCT02213900	PHASE4	COMPLETED	Preventing Post-Operative Delirium in Patients Undergoing a Pneumonectomy, Esophagectomy or Thoracotomy
NCT02336308	PHASE4	WITHDRAWN	A Randomized, Double-Blind Study of Placebo vs. Ketamine For Use During Dressing Changes in Critically Ill Burn Patients
NCT02366390	PHASE4	COMPLETED	Dialogue Aimed at Reducing Anxiety in Patients With Severe COPD
NCT02372110	PHASE4	COMPLETED	Disentangling Anxiety Sensitivity and Anxiety-induced Physiological Stress Response
NCT02545634	PHASE4	UNKNOWN	Effects of a Probiotic Supplement on Symptoms of Attention Deficit Hyperactivity Disorder and Anxiety in Children