PAX6

Summary

PAX6 (paired box 6, HGNC:8620) is a protein-coding gene on chromosome 11p13, encoding Paired box protein Pax-6 (P26367). Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.

This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter’s anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain.

Source: NCBI Gene 5080 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PAX6-related ocular dysgenesis (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 842 total — 333 pathogenic, 80 likely-pathogenic
• Phenotypes (HPO): 108
• Transcription factor: yes — 178 downstream targets (CollecTRI)
• MANE Select transcript: NM_001368894

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8620
Approved symbol	PAX6
Name	paired box 6
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	D11S812E, AN, WAGR
Ensembl gene	ENSG00000007372
Ensembl biotype	protein_coding
OMIM	607108
Entrez	5080

Gene structure

Transcript identifiers

Ensembl transcripts: 81 — 55 protein_coding, 15 retained_intron, 10 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000241001, ENST00000379107, ENST00000379109, ENST00000379111, ENST00000379115, ENST00000379123, ENST00000379129, ENST00000379132, ENST00000419022, ENST00000423822, ENST00000438681, ENST00000455099, ENST00000464174, ENST00000470027, ENST00000471303, ENST00000474783, ENST00000481563, ENST00000494377, ENST00000524853, ENST00000527769, ENST00000530373, ENST00000530714, ENST00000531910, ENST00000532175, ENST00000532916, ENST00000533156, ENST00000533333, ENST00000534353, ENST00000534390, ENST00000606377, ENST00000638250, ENST00000638278, ENST00000638346, ENST00000638629, ENST00000638685, ENST00000638696, ENST00000638755, ENST00000638762, ENST00000638802, ENST00000638853, ENST00000638878, ENST00000638913, ENST00000638914, ENST00000638963, ENST00000638965, ENST00000639006, ENST00000639034, ENST00000639054, ENST00000639061, ENST00000639079, ENST00000639109, ENST00000639203, ENST00000639386, ENST00000639394, ENST00000639409, ENST00000639548, ENST00000639916, ENST00000639920, ENST00000639943, ENST00000639950, ENST00000640038, ENST00000640125, ENST00000640172, ENST00000640242, ENST00000640251, ENST00000640287, ENST00000640335, ENST00000640368, ENST00000640431, ENST00000640460, ENST00000640610, ENST00000640613, ENST00000640617, ENST00000640684, ENST00000640735, ENST00000640766, ENST00000640819, ENST00000640872, ENST00000640963, ENST00000640975, ENST00000643871

RefSeq mRNA: 51 — MANE Select: NM_001368894 NM_000280, NM_001127612, NM_001258462, NM_001258463, NM_001258464, NM_001258465, NM_001310158, NM_001310159, NM_001310160, NM_001310161, NM_001368887, NM_001368888, NM_001368889, NM_001368890, NM_001368891, NM_001368892, NM_001368893, NM_001368894, NM_001368899, NM_001368900, NM_001368901, NM_001368902, NM_001368903, NM_001368904, NM_001368905, NM_001368906, NM_001368907, NM_001368908, NM_001368909, NM_001368910, NM_001368911, NM_001368912, NM_001368913, NM_001368914, NM_001368915, NM_001368916, NM_001368917, NM_001368918, NM_001368919, NM_001368920, NM_001368921, NM_001368922, NM_001368923, NM_001368924, NM_001368925, NM_001368926, NM_001368927, NM_001368928, NM_001368929, NM_001368930, NM_001604

CCDS: CCDS31451, CCDS31452, CCDS86189, CCDS86190, CCDS91455, CCDS91456

Canonical transcript exons

ENST00000640368 — 14 exons

Exon	Start	End
ENSE00001004114	31810828	31811015
ENSE00001098662	31806849	31806925
ENSE00002523992	31806402	31806462
ENSE00003512677	31801871	31801912
ENSE00003523920	31801561	31801776
ENSE00003602163	31802704	31802834
ENSE00003695229	31800691	31800856
ENSE00003696657	31794032	31794114
ENSE00003697187	31793652	31793802
ENSE00003698739	31794630	31794788
ENSE00003700637	31790710	31790860
ENSE00003701932	31793438	31793553
ENSE00003807426	31811115	31811322
ENSE00003810826	31789026	31790019

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.54.

FANTOM5 (CAGE): breadth broad, TPM avg 23.5849 / max 2215.4583, expressed in 624 samples.

FANTOM5 promoters (31 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119153	5.7936	486
119155	4.3160	412
119156	3.7845	354
119162	1.9911	249
119152	1.8051	325
119154	1.1344	329
119151	1.1225	230
119160	0.3532	131
119134	0.3430	137
119144	0.3395	111

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	99.54	gold quality
type B pancreatic cell	CL:0000169	99.28	gold quality
ventricular zone	UBERON:0003053	99.28	gold quality
paraflocculus	UBERON:0005351	99.06	gold quality
ganglionic eminence	UBERON:0004023	98.45	gold quality
cerebellum	UBERON:0002037	97.88	gold quality
cerebellar vermis	UBERON:0004720	97.76	gold quality
cerebellar cortex	UBERON:0002129	97.72	gold quality
cerebellar hemisphere	UBERON:0002245	97.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.29	gold quality
eye	UBERON:0000970	97.21	gold quality
islet of Langerhans	UBERON:0000006	97.19	gold quality
pons	UBERON:0000988	95.22	gold quality
embryo	UBERON:0000922	94.83	gold quality
lateral globus pallidus	UBERON:0002476	93.19	gold quality
CA1 field of hippocampus	UBERON:0003881	91.85	gold quality
middle frontal gyrus	UBERON:0002702	91.45	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.39	gold quality
pigmented layer of retina	UBERON:0001782	88.74	gold quality
retina	UBERON:0000966	88.72	gold quality
entorhinal cortex	UBERON:0002728	88.16	gold quality
putamen	UBERON:0001874	87.36	gold quality
temporal lobe	UBERON:0001871	87.33	gold quality
caudate nucleus	UBERON:0001873	87.32	gold quality
amygdala	UBERON:0001876	87.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.93	gold quality
frontal pole	UBERON:0002795	85.80	gold quality
medulla oblongata	UBERON:0001896	85.75	gold quality
cingulate cortex	UBERON:0003027	85.08	gold quality
anterior cingulate cortex	UBERON:0009835	85.04	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1743.90
E-MTAB-7316	yes	1478.91
E-MTAB-10485	yes	1004.16
E-GEOD-83139	yes	768.92
E-MTAB-10018	yes	166.23
E-HCAD-5	yes	44.89
E-GEOD-137537	yes	30.50
E-MTAB-5061	yes	17.96
E-GEOD-93593	yes	15.87
E-ENAD-27	yes	4.37
E-GEOD-125970	yes	4.35
E-MTAB-6108	no	894.59
E-MTAB-6911	no	486.44
E-GEOD-81608	no	8.38
E-HCAD-31	no	6.56

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

178 targets.

Target	Regulation
ABCC8
ADAM2
AKT1
ALDH3A1	Activation
ANGPTL7	Activation
AR
ARAP1
ASCL1	Repression
ATOH1	Activation
ATOH7	Activation
BCL9	Activation
BCL9L	Activation
BTC
CD40
CD74
CDH2	Unknown
CDH4	Activation
CDK6	Repression
CDKN1A	Activation
CDKN1B	Activation
CDKN1C	Activation
CDKN2A	Activation
CDKN2B
CDKN2D	Activation
CEL
CLU	Activation
CNBP	Unknown
CNTN2
CRYAA	Unknown
CRYAB	Activation

JASPAR motifs

Motif	Name	Family
MA0069.1	PAX6	Paired plus homeo domain

JASPAR matrix evidence (PMIDs): PMID:8132558

Upstream regulators (CollecTRI, top): BHLHE22, CRX, CTCF, EOMES, FEZF1, FOXA2, FOXG1, GLIS3, INSM1, LHX2, MEIS1, MEIS2, MITF, MYB, NANOG, NEUROD1, NEUROG2, NEUROG3, NRL, OTX2, PAX2, PAX3, PAX6, PBX1, PDX1, PHOX2B, POU4F2, POU5F1, PROX1, PYGO2, SIRT1, SIX3, SMAD3, SOX1, SOX2, SP1, SP8, TCF12, TFCP2, TGFB1

miRNA regulators (miRDB)

160 targeting PAX6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 40)

• HoxB1 interacts with Pax6 and enhances its transcriptional activity. This interaction was modeled on a demonstrated interaction between zebrafish Pax6 and human HoxB1. (PMID:11069920)
• Pbx1 interacts with Pax6 and enhances its transcriptional activity. This interaction was modeled on a demonstrated interaction between zebrafish Pax6 and human Pbx1. (PMID:11069920)
• New 3’ elements control Pax6 expression in the developing pretectum, neural retina and olfactory region (PMID:11850181)
• mDia influences Pax6-induced transcriptional activity and axonal pathfinding in a way opposite from ROCK (Rho kinase) and that it may act via Pax6 to modulate early neuronal development (PMID:12324464)
• Independent modifying factors underlie the variability of the different phenotypic features of the PAX6 mutation in aniridia. (PMID:12325030)
• Mutations of the PAX6 gene were detected in patients with a variety of optic-nerve malformations. (PMID:12721955)
• in 24 humans heterozygous for defined PAX6 mutations, widespread structural abnormalities including absence of the pineal gland and unilateral polymicrogyria were demonstrated (PMID:12731001)
• We report for the first time the identification of PAX6 gene mutations in Indian aniridia patients. (PMID:12789139)
• PAX6 gene mutations are associated with aniridia (PMID:12868034)
• This study confirms that foveal hypoplasia in the so-called isolated form have a similar origin as in aniridia namely PAX6 mutation and that it is a symptom in all cases while the iris anomaly may be variable. (PMID:12953159)
• The possible role of PAX6 includes neurodevelopmental roles not only in visual and olfactory sensory domains but also in higher-order auditory processing. (PMID:14872040)
• The brain functional differences in humans with PAX6 mutation that are compatible both with anatomical abnormalities in the same subjects. (PMID:15066147)
• Patients with PAX6 gene mutations and agenesis of the anterior commissure performed more poorly on measures of working memory than those without this abnormality, suggesting the anterior commissure may play a role in cognitive processing (PMID:15079031)
• Study supports the hypothesis that a mutation in the PAX6 gene correlates with expression of aniridia. (PMID:15086958)
• These results are consistent with deficient auditory interhemispheric transfer in patients with a PAX6 mutation, which may be attributable to structural and/or functional abnormalities of the anterior commisure and corpus callosum. (PMID:15389894)
• The association of anterior segment anomalies and foveal hypoplasia with one of the slightest alterations of the PAX6 protein described to date confirms the association of variant phenotypes (PMID:15629294)
• Epidermal growth factor-induced proliferation requires down-regulation of Pax6 in corneal epithelial cells (PMID:15659382)
• Pax6(+5a) induces a developmental cascade in the prospective fovea, area centralis or visual streak region that leads to the formation of a retinal architecture bearing densely packed visual cells. (PMID:15677484)
• Transient overexpression of PAX6 via adenovirus suppressed cell growth by increasing the number of cells in G1 and by decreasing the number of cells in S-phase, and later on caused a dramatic level of cell death. (PMID:15735909)
• central roles in neural retina transdifferentiation (PMID:15757974)
• A novel PAX6 gene mutation was identified in a Chinese aniridia family. This mutation may also contribute to congenital cataracts in these aniridia patients. (PMID:15889018)
• The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles (PMID:15918896)
• PAX6 interacts with HOMER3, DNCL1, and TRIM11. Three C-terminal PAX6 mutations, previously identified in patients with eye malformations, all reduced or abolished the interactions. (PMID:16098226)
• Pax6 regulation of Optimedin in the eye and brain may directly affect multiple developmental processes, including cell migration and axon growth (PMID:16115881)
• HIPK2 is an upstream protein kinase for Pax6 that may modulate Pax6-mediated transcriptional regulation (PMID:16407227)
• X-ray analysis of the Pax6 paired domain bound to the Pax6 gene enhancer (PMID:16511221)
• Truncating PAX6 mutations and ocular phenotypes is associated with aniridia (PMID:16543198)
• Two sequence variations in PAX6 gene. These missense mutations may uniquely alter structure and expression of PAX6 protein, resulting in distinct clinical phenotypes. (PMID:16604056)
• 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)
• Four novel mutations including c.141+1G>A, c.184-3C>G, c.542C>A (Ser181X), and c.562C>T (Gln188X) and one known mutation c.120C>A (Cys40X) were identified in PAX6 of five unrelated patients with aniridia. (PMID:16785853)
• New deletions and an insertion create frameshifts predicted to introduce premature termination codons into the PAX6 reading frame. The genetic alterations are predicted to lead to loss-of-function mutations segregating in autosomal dominant manner. (PMID:16803629)
• potential effect of the PAX6 mutation on the mtDNA mutation rate (PMID:17031679)
• To our knowledge, this is the first mutation of PAX6 gene reported in association with a Gillespie-like syndrome. (PMID:17148041)
• the proliferation of cortical progenitors is sensitive to altered Pax6 levels (PMID:17202185)
• PAX6 over-expression in low PAX6-expressing glioma cells attenuated recovery of growth after detachment-induced stress, and intracellular reactive oxygen species levels increased following cell detachment. (PMID:17318412)
• Mutation of PAX6 gene can result in the occurrence of congenital aniridia. (PMID:17415970)
• We identified three mutations associated with aniridia phenotypes (Q179X, C40X, and V48fsX53). The three other mutations reported here cause non-aniridia ocular phenotypes associated in some cases with neurological anomalies. (PMID:17417613)
• Finds children with PAX6 mutations may have auditory interhemispheric transfer deficits and difficulty localizing sound and understanding speech in noisy backgrounds even when there is a normal audiogram. (PMID:17485622)
• PAX6 point mutations and deletions can cause aniridia. (PMID:17568989)
• Screening of PAX6 in patients with suspected Gillespie syndrome should be performed with up-to-date methodology. (PMID:17595013)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pax6b	ENSDARG00000045936
danio_rerio	pax6a	ENSDARG00000103379
mus_musculus	Pax6	ENSMUSG00000027168
rattus_norvegicus	Pax6	ENSRNOG00000004410

Paralogs (50): ARX (ENSG00000004848), 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), OTX2 (ENSG00000165588), 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

Paired box protein Pax-6 — P26367 (reviewed: P26367)

Alternative names: Aniridia type II protein, Oculorhombin

All UniProt accessions (36): P26367, A0A1W2PNS7, A0A1W2PP27, A0A1W2PP89, A0A1W2PPG3, A0A1W2PPH0, A0A1W2PPJ2, A0A1W2PPM5, A0A1W2PPN2, A0A1W2PQ31, A0A1W2PQA8, A0A1W2PQG3, A0A1W2PQG7, A0A1W2PQJ8, A0A1W2PQL7, A0A1W2PQM7, A0A1W2PQW3, A0A1W2PR58, A0A1W2PRA4, A0A1W2PRA8, A0A1W2PRG3, A0A1W2PRH6, A0A1W2PRS6, A0A1W2PRU4, A0A1W2PRW7, A0A1W2PS91, A0A1W2PSA8, A0A1W2PSB5, A0A1X7SBT0, B1B1I8, B1B1I9, B1B1J0, D1KF47, E9PKM0, F1T0F8, Q66SS1

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas. Required for the differentiation of pancreatic islet alpha cells. Competes with PAX4 in binding to a common element in the glucagon, insulin and somatostatin promoters. Regulates specification of the ventral neuron subtypes by establishing the correct progenitor domains. Acts as a transcriptional repressor of NFATC1-mediated gene expression.

Subunit / interactions. Interacts with MAF and MAFB. Interacts with TRIM11; this interaction leads to ubiquitination and proteasomal degradation, as well as inhibition of transactivation, possibly in part by preventing PAX6 binding to consensus DNA sequences. Interacts with TLE6/GRG6.

Subcellular location. Nucleus Nucleus Nucleus.

Tissue specificity. Expressed in lymphoblasts. Weakly expressed in lymphoblasts.

Post-translational modifications. Ubiquitinated by TRIM11, leading to ubiquitination and proteasomal degradation.

Disease relevance. Aniridia 1 (AN1) [MIM:106210] A congenital, bilateral, panocular disorder characterized by complete absence of the iris or extreme iris hypoplasia. Aniridia is not just an isolated defect in iris development but it is associated with macular and optic nerve hypoplasia, cataract, corneal changes, nystagmus. Visual acuity is generally low but is unrelated to the degree of iris hypoplasia. Glaucoma is a secondary problem causing additional visual loss over time. The disease is caused by variants affecting the gene represented in this entry. Anterior segment dysgenesis 5 (ASGD5) [MIM:604229] A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. The disease is caused by variants affecting the gene represented in this entry. Foveal hypoplasia 1 (FVH1) [MIM:136520] An isolated form of foveal hypoplasia, a developmental defect of the eye defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Clinical features include absence of foveal pit on optical coherence tomography, absence of foveal hyperpigmentation, absence of foveal avascularity, absence of foveal and macular reflexes, decreased visual acuity, and nystagmus. Anterior segment anomalies and cataract are observed in some FVH1 patients. The disease is caused by variants affecting the gene represented in this entry. Keratitis hereditary (KERH) [MIM:148190] An ocular disorder characterized by corneal opacification, recurrent stromal keratitis and vascularization. The disease is caused by variants affecting the gene represented in this entry. Microphthalmia/coloboma 12 (MCOPCB12) [MIM:120200] A form of colobomatous microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like coloboma, opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). MCOPCB12 is an autosomal dominant form characterized by inter- and intrafamilial variability. Some patients also exhibit neurodevelopmental anomalies. The disease is caused by variants affecting the gene represented in this entry. Coloboma of optic nerve (COLON) [MIM:120430] An ocular defect that is due to malclosure of the fetal intraocular fissure affecting the optic nerve head. In some affected individuals, it appears as enlargement of the physiologic cup with severely affected eyes showing huge cavities at the site of the disk. The disease is caused by variants affecting the gene represented in this entry. Bilateral optic nerve hypoplasia (BONH) [MIM:165550] A congenital anomaly in which the optic disk appears abnormally small. It may be an isolated finding or part of a spectrum of anatomic and functional abnormalities that includes partial or complete agenesis of the septum pellucidum, other midline brain defects, cerebral anomalies, pituitary dysfunction, and structural abnormalities of the pituitary. The disease is caused by variants affecting the gene represented in this entry. Aniridia 2 (AN2) [MIM:617141] A form of aniridia, a congenital, bilateral, panocular disorder characterized by complete absence of the iris or extreme iris hypoplasia. Aniridia is not just an isolated defect in iris development but it is associated with macular and optic nerve hypoplasia, cataract, corneal changes, nystagmus. Visual acuity is generally low but is unrelated to the degree of iris hypoplasia. Glaucoma is a secondary problem causing additional visual loss over time. The gene represented in this entry is involved in disease pathogenesis. A mutation in a PAX6 long-range cis-regulatory element, known as SIMO, affects PAX6 expression in the developing eye and has pathological consequences. The mutation is located in ELP4 intron 9, 150 kb downstream of PAX6.

Similarity. Belongs to the paired homeobox family.

Isoforms (3)

UniProt ID	Names	Canonical?
P26367-1	1	yes
P26367-2	5a, Pax6-5a
P26367-3	3, Pax6-5A,6*

RefSeq proteins (51): NP_000271, NP_001121084, NP_001245391, NP_001245392, NP_001245393, NP_001245394, NP_001297087, NP_001297088, NP_001297089, NP_001297090, NP_001355816, NP_001355817, NP_001355818, NP_001355819, NP_001355820, NP_001355821, NP_001355822, NP_001355823, NP_001355828, NP_001355829, NP_001355830, NP_001355831, NP_001355832, NP_001355833, NP_001355834, NP_001355835, NP_001355836, NP_001355837, NP_001355838, NP_001355839, NP_001355840, NP_001355841, NP_001355842, NP_001355843, NP_001355844, NP_001355845, NP_001355846, NP_001355847, NP_001355848, NP_001355849, NP_001355850, NP_001355851, NP_001355852, NP_001355853, NP_001355854, NP_001355855, NP_001355856, NP_001355857, NP_001355858, NP_001355859, NP_001595 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001523	Paired_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR043182	PAIRED_DNA-bd_site	Conserved_site
IPR043565	PAX_fam	Family

Pfam: PF00046, PF00292

UniProt features (71 total): sequence variant 46, helix 9, region of interest 5, strand 3, DNA-binding region 2, sequence conflict 2, chain 1, turn 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6PAX	X-RAY DIFFRACTION	2.5
2CUE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26367-F1	69.35	0.41

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-9823739	Formation of the anterior neural plate

MSigDB gene sets: 705 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, AHRARNT_01, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, E2F_Q4, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, MYAATNNNNNNNGGC_UNKNOWN, RRAGTTGT_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_GLAND_MORPHOGENESIS

GO Biological Process (86): negative regulation of transcription by RNA polymerase II (GO:0000122), establishment of mitotic spindle orientation (GO:0000132), blood vessel development (GO:0001568), eye development (GO:0001654), cell fate determination (GO:0001709), neuron migration (GO:0001764), positive regulation of neuroblast proliferation (GO:0002052), lens development in camera-type eye (GO:0002088), type B pancreatic cell differentiation (GO:0003309), pancreatic A cell development (GO:0003322), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), smoothened signaling pathway (GO:0007224), nervous system development (GO:0007399), neuroblast proliferation (GO:0007405), negative regulation of neuroblast proliferation (GO:0007406), axon guidance (GO:0007411), central nervous system development (GO:0007417), brain development (GO:0007420), sensory organ development (GO:0007423), salivary gland morphogenesis (GO:0007435), visual perception (GO:0007601), response to wounding (GO:0009611), regulation of asymmetric cell division (GO:0009786), animal organ morphogenesis (GO:0009887), dorsal/ventral axis specification (GO:0009950), positive regulation of gene expression (GO:0010628), ventral spinal cord development (GO:0021517), spinal cord motor neuron cell fate specification (GO:0021520), ventral spinal cord interneuron specification (GO:0021521), oligodendrocyte cell fate specification (GO:0021778), cerebral cortex regionalization (GO:0021796), forebrain dorsal/ventral pattern formation (GO:0021798), commitment of neuronal cell to specific neuron type in forebrain (GO:0021902), forebrain-midbrain boundary formation (GO:0021905), somatic motor neuron fate commitment (GO:0021917), pituitary gland development (GO:0021983), habenula development (GO:0021986), signal transduction involved in regulation of gene expression (GO:0023019)

GO Molecular Function (21): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coregulator binding (GO:0001221), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), RNA binding (GO:0003723), protein kinase binding (GO:0019901), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), histone acetyltransferase binding (GO:0035035), co-SMAD binding (GO:0070410), R-SMAD binding (GO:0070412), HMG box domain binding (GO:0071837), sequence-specific double-stranded DNA binding (GO:1990837), chromatin binding (GO:0003682), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Incretin synthesis, secretion, and inactivation	2
Regulation of beta-cell development	1
Activation of HOX genes during differentiation	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	5
cellular anatomical structure	5
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
anatomical structure development	2
generation of neurons	2
neuroblast proliferation	2
regulation of neuroblast proliferation	2
regulation of DNA-templated transcription	2
system development	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
nucleic acid binding	2
SMAD binding	2
binding	2
negative regulation of DNA-templated transcription	1
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
vasculature development	1
sensory organ development	1
visual system development	1
cell fate commitment	1
cellular developmental process	1
cell migration	1
positive regulation of neurogenesis	1
positive regulation of neural precursor cell proliferation	1
camera-type eye development	1
endocrine pancreas development	1
enteroendocrine cell differentiation	1
epithelial cell development	1
pancreatic A cell differentiation	1
chromatin organization	1
DNA-templated transcription	1
cell surface receptor signaling pathway	1
neural precursor cell proliferation	1
negative regulation of neurogenesis	1
negative regulation of neural precursor cell proliferation	1
axonogenesis	1
neuron projection guidance	1
nervous system development	1

Protein interactions and networks

STRING

4248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAX6	DCAF7	P61962	993
PAX6	SOX2	P48431	965
PAX6	BANF1	O75531	952
PAX6	SIX3	O95343	927
PAX6	TBR1	Q16650	907
PAX6	NEUROG2	Q9H2A3	901
PAX6	MAF	O75444	893
PAX6	SOX1	O00570	884
PAX6	MITF	O75030	880
PAX6	ISL1	P20663	879
PAX6	OLIG2	Q13516	868
PAX6	NKX2-2	O95096	868
PAX6	NES	P48681	859
PAX6	P4HTM	Q9NXG6	858
PAX6	FOXG1	P55315	843

IntAct

339 interactions, top by confidence:

A	B	Type	Score
PAX6	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
PAX6	CXorf38	psi-mi:“MI:0915”(physical association)	0.560
PAX6	TLK2	psi-mi:“MI:0915”(physical association)	0.560
PAX6	CINP	psi-mi:“MI:0915”(physical association)	0.560
ZBED1	PAX6	psi-mi:“MI:0915”(physical association)	0.560
PAX6	POLR3GL	psi-mi:“MI:0915”(physical association)	0.560
PAX6	PIN1	psi-mi:“MI:0915”(physical association)	0.560
PAX6	ZNF410	psi-mi:“MI:0915”(physical association)	0.560
PAX6	MORN3	psi-mi:“MI:0915”(physical association)	0.560
PAX6	PPIL4	psi-mi:“MI:0915”(physical association)	0.560
PAX6	C2CD6	psi-mi:“MI:0915”(physical association)	0.560
PAX6	QRICH1	psi-mi:“MI:0915”(physical association)	0.560
PAX6	CKS1B	psi-mi:“MI:0915”(physical association)	0.560
PAX6	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
PAX6	LYSMD1	psi-mi:“MI:0915”(physical association)	0.560
PAX6	KCTD7	psi-mi:“MI:0915”(physical association)	0.560
PAX6	THOC1	psi-mi:“MI:0915”(physical association)	0.560
PAX6	SPDYC	psi-mi:“MI:0915”(physical association)	0.560
ARIH2	PAX6	psi-mi:“MI:0915”(physical association)	0.560
PAX6	CHAF1A	psi-mi:“MI:0915”(physical association)	0.560
GCM2	PAX6	psi-mi:“MI:0915”(physical association)	0.560
PAX6	NFYC	psi-mi:“MI:0915”(physical association)	0.560
PAX6	NCDN	psi-mi:“MI:0915”(physical association)	0.560
KANK2	PAX6	psi-mi:“MI:0915”(physical association)	0.560
PAX6	SAE1	psi-mi:“MI:0915”(physical association)	0.560
PAX6	TRIP10	psi-mi:“MI:0915”(physical association)	0.560
PAX6	BANP	psi-mi:“MI:0915”(physical association)	0.560
PAX6	UBE2F	psi-mi:“MI:0915”(physical association)	0.560
PAX6	EIF1AD	psi-mi:“MI:0915”(physical association)	0.560
SLC12A8	PAX6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (384): IPO13 (Two-hybrid), APOB (Affinity Capture-MS), EPB41L2 (Affinity Capture-MS), PCNT (Affinity Capture-MS), RAN (Affinity Capture-MS), RBM4 (Affinity Capture-MS), GMPS (Affinity Capture-MS), UBE2M (Affinity Capture-MS), TRAP1 (Affinity Capture-MS), AP5M1 (Affinity Capture-MS), RBM26 (Affinity Capture-MS), MARCKSL1 (Affinity Capture-MS), FYCO1 (Affinity Capture-MS), TMEM189 (Affinity Capture-MS), PAX6 (Reconstituted Complex)

ESM2 similar proteins: A0A1U8QIH0, A0A1U8QVN4, A0A2R6S148, A0A4D6QCQ2, A0A6S6AAU0, B0D0T8, E0CJS3, G4N7X0, G5EDS1, L7R9Z0, O13493, O73917, P09082, P23760, P24610, P26367, P26630, P47238, P63015, P63016, P80073, P81391, P9WEF9, Q01371, Q1LZF1, Q22812, Q24JK1, Q2QZJ8, Q2VL61, Q4JL76, Q4JL84, Q65ZG6, Q6K1S6, Q7K0S9, Q7XBH4, Q96276, Q9FDW1, Q9FJP2, Q9LDE1, Q9LSI7

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

13 interactions.

A	Effect	B	Mechanism
HIPK2	“up-regulates activity”	PAX6	phosphorylation
PAX6	“up-regulates quantity by expression”	PAX6	“transcriptional regulation”
TGFB1	“down-regulates quantity by repression”	PAX6	“transcriptional regulation”
SMAD3	“down-regulates activity”	PAX6	binding
POU5F1	“down-regulates quantity by repression”	PAX6	“transcriptional regulation”
NANOG	“down-regulates quantity by repression”	PAX6	“transcriptional regulation”
PDHX	“down-regulates activity”	PAX6	binding
PAX6	“up-regulates quantity by expression”	GCG	“transcriptional regulation”
PAX6	“form complex”	CDX2/PAX6/P300	binding
PAX6	“up-regulates quantity by expression”	CTNND2	“transcriptional regulation”
PAX6	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	333
Likely pathogenic	80
Uncertain significance	191
Likely benign	143
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1023138	NM_001368894.2(PAX6):c.275T>A (p.Val92Glu)	Pathogenic
1069925	NM_001368894.2(PAX6):c.790_806del (p.Pro264fs)	Pathogenic
1070548	NM_001368894.2(PAX6):c.483del (p.Met162fs)	Pathogenic
1072682	NC_000011.9:g.(?31804921)(31816377_?)del	Pathogenic
1075087	NM_001368894.2(PAX6):c.720del (p.Glu242fs)	Pathogenic
1075401	NM_001368894.2(PAX6):c.52G>A (p.Gly18Arg)	Pathogenic
1183523	NM_001368894.2(PAX6):c.808-1G>T	Pathogenic
1187268	NM_001368894.2(PAX6):c.961del (p.Ser321fs)	Pathogenic
1190713	NM_001368894.2(PAX6):c.54del (p.Arg19fs)	Pathogenic
1254586	NM_001368894.2(PAX6):c.1090C>T (p.Gln364Ter)	Pathogenic
1275762	NM_001368894.2(PAX6):c.225del (p.Tyr74_Tyr75insTer)	Pathogenic
1328482	NM_001368894.2(PAX6):c.956del (p.Pro319fs)	Pathogenic
1342028	NM_001368894.2(PAX6):c.537_541dup (p.Ser181Ter)	Pathogenic
1372939	NM_001368894.2(PAX6):c.829del (p.Ala277fs)	Pathogenic
1389199	NM_001368894.2(PAX6):c.1061del (p.Asn354fs)	Pathogenic
1390086	NM_001368894.2(PAX6):c.1086del (p.Ser363fs)	Pathogenic
1429880	NM_001368894.2(PAX6):c.385_386dup (p.Asp129fs)	Pathogenic
1434624	NM_001368894.2(PAX6):c.399+2T>C	Pathogenic
1434660	NM_001368894.2(PAX6):c.1074+1G>C	Pathogenic
1451194	NM_001368894.2(PAX6):c.709G>T (p.Glu237Ter)	Pathogenic
1452270	NM_001368894.2(PAX6):c.690del (p.Phe231fs)	Pathogenic
1452288	NC_000011.9:g.(?31824326)(31832375_?)del	Pathogenic
1452757	NM_001368894.2(PAX6):c.225C>A (p.Tyr75Ter)	Pathogenic
1457769	NM_001368894.2(PAX6):c.425G>C (p.Arg142Pro)	Pathogenic
1458846	NM_001368894.2(PAX6):c.400-2A>T	Pathogenic
1459052	NM_001368894.2(PAX6):c.417del (p.Val140fs)	Pathogenic
1459449	NM_001368894.2(PAX6):c.1225G>A (p.Gly409Arg)	Pathogenic
1459450	NM_001368894.2(PAX6):c.802_807+9del	Pathogenic
1459661	NM_001368894.2(PAX6):c.399+1G>C	Pathogenic
1691773	NM_000280.6(PAX6):c.143T>C (p.Val48Ala)	Pathogenic

SpliceAI

2564 predictions. Top by Δscore:

Variant	Effect	Δscore
11:31790858:GGG:G	acceptor_gain	1.0000
11:31790859:GG:G	acceptor_gain	1.0000
11:31790861:C:CC	acceptor_gain	1.0000
11:31790863:G:C	acceptor_gain	1.0000
11:31793432:ACTT:A	donor_loss	1.0000
11:31793434:TTA:T	donor_loss	1.0000
11:31793435:TAC:T	donor_loss	1.0000
11:31793436:A:AC	donor_gain	1.0000
11:31793436:A:T	donor_loss	1.0000
11:31793437:C:A	donor_loss	1.0000
11:31793437:C:CC	donor_gain	1.0000
11:31793437:CTTG:C	donor_gain	1.0000
11:31793549:GGAAA:G	acceptor_gain	1.0000
11:31793550:GAAA:G	acceptor_gain	1.0000
11:31793551:AAA:A	acceptor_gain	1.0000
11:31793551:AAAC:A	acceptor_loss	1.0000
11:31793552:AA:A	acceptor_gain	1.0000
11:31793553:AC:A	acceptor_loss	1.0000
11:31793554:C:CC	acceptor_gain	1.0000
11:31793554:CTGAG:C	acceptor_loss	1.0000
11:31793555:T:G	acceptor_loss	1.0000
11:31793648:TTAC:T	donor_loss	1.0000
11:31793649:TACC:T	donor_loss	1.0000
11:31793650:A:AC	donor_gain	1.0000
11:31793651:C:CC	donor_gain	1.0000
11:31793798:CATAC:C	acceptor_gain	1.0000
11:31793800:TAC:T	acceptor_gain	1.0000
11:31793800:TACC:T	acceptor_loss	1.0000
11:31793801:ACCT:A	acceptor_loss	1.0000
11:31793803:CTG:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000041362 (11:31818024 C>A), RS1000160042 (11:31800630 T>A,C), RS1000190930 (11:31804206 T>C), RS1000277040 (11:31796752 G>C), RS1000286801 (11:31796983 G>A,T), RS1000374812 (11:31798176 C>T), RS1000401238 (11:31791103 G>A), RS1000583748 (11:31802926 G>A), RS1000659731 (11:31809936 GC>G,GCC), RS1000728210 (11:31808129 C>G), RS1000780438 (11:31808439 T>C), RS1000822508 (11:31809604 A>C), RS1000878472 (11:31790260 G>A), RS1000910205 (11:31793155 C>T), RS1000987450 (11:31814069 C>G)

Disease associations

OMIM: gene MIM:607108 | disease phenotypes: MIM:604229, MIM:106210, MIM:120430, MIM:120200, MIM:136520, MIM:148190, MIM:165550, MIM:194072, MIM:206700, MIM:107250

GenCC curated gene-disease

Disease	Classification	Inheritance
aniridia 1	Definitive	Autosomal dominant
Peters anomaly	Definitive	Autosomal dominant
diabetes mellitus	Strong	Autosomal dominant
PAX6-related ocular dysgenesis	Strong	Autosomal dominant
autosomal dominant keratitis	Supportive	Autosomal dominant
aniridia-cerebellar ataxia-intellectual disability syndrome	Supportive	Autosomal dominant
isolated optic nerve hypoplasia	Supportive	Autosomal dominant
foveal hypoplasia-presenile cataract syndrome	Supportive	Autosomal dominant
isolated aniridia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
PAX6-related ocular dysgenesis	Definitive	AD

Mondo (20): Peters anomaly (MONDO:0011414), aniridia 1 (MONDO:0024507), coloboma of optic nerve (MONDO:0007354), coloboma, ocular, autosomal dominant (MONDO:0007350), aniridia (MONDO:0019172), foveal hypoplasia 1 (MONDO:0007628), autosomal dominant keratitis (MONDO:0007848), isolated optic nerve hypoplasia (MONDO:0008136), WAGR syndrome (MONDO:0008681), coloboma of iris (MONDO:0020356), PAX6-related ocular dysgenesis (MONDO:0800183), aniridia-cerebellar ataxia-intellectual disability syndrome (MONDO:0008795), coloboma (MONDO:0001476), microphthalmia (MONDO:0021129), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764)

Orphanet (17): Isolated aniridia (Orphanet:250923), Peters anomaly (Orphanet:708), Morning glory disc anomaly (Orphanet:35737), Coloboma of optic disc (Orphanet:98947), Foveal hypoplasia-presenile cataract syndrome (Orphanet:2253), Autosomal dominant keratitis (Orphanet:2334), Isolated optic nerve hypoplasia (Orphanet:637061), WAGR syndrome (Orphanet:893), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Coloboma of iris (Orphanet:98944), Aniridia-cerebellar ataxia-intellectual disability syndrome (Orphanet:1065), OBSOLETE: Ocular coloboma (Orphanet:194), Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Anterior segment developmental anomaly (Orphanet:88632), OBSOLETE: Aniridia (Orphanet:77)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000062	Ambiguous genitalia
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000112	Nephropathy
HP:0000130	Abnormality of the uterus
HP:0000142	Abnormal vagina morphology
HP:0000150	Gonadoblastoma
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000478	Abnormality of the eye
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000491	Keratitis
HP:0000501	Glaucoma
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000523	Subcapsular cataract
HP:0000526	Aniridia
HP:0000539	Abnormality of refraction
HP:0000541	Retinal detachment
HP:0000558	Rieger anomaly

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001415_6	Body mass index	8.000000e-08
GCST004076_21	Optic disc area	5.000000e-11
GCST004076_7	Optic disc area	2.000000e-10
GCST004904_236	Body mass index	1.000000e-08
GCST005839_4	Depression	1.000000e-09
GCST006041_27	Major depressive disorder	4.000000e-07
GCST006940_49	Neurociticism	7.000000e-10
GCST006941_2	Irritable mood	1.000000e-09
GCST006950_25	Feeling worry	3.000000e-09
GCST007094_237	Diastolic blood pressure	1.000000e-09
GCST007098_29	Diastolic blood pressure	3.000000e-06
GCST007099_196	Systolic blood pressure	7.000000e-08
GCST007709_282	General factor of neuroticism	1.000000e-10
GCST007709_283	General factor of neuroticism	9.000000e-09
GCST009600_24	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-09
GCST010002_234	Refractive error	2.000000e-49

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007660	neuroticism measurement
EFO:0009594	irritability measurement
EFO:0009589	worry measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D015783	Aniridia	C11.250.060; C11.270.060; C11.941.375.060; C16.131.384.079; C16.320.290.078
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008850	Microphthalmos	C11.250.566; C16.131.384.666
D017624	WAGR Syndrome	C04.557.435.595.950; C04.588.945.947.535.585.950; C04.700.900.950; C10.597.606.360.969; C11.250.060.950; C11.270.060.950; C11.941.375.060.950; C12.050.351.875.253.096.875; C12.050.351.937.820.535.585.950; C12.050.351.968.419.473.585.950; C12.200.706.316.096.875; C12.200.758.820.750.585.950; C12.200.777.419.473.585.950; C12.800.316.096.875; C12.900.820.535.585.950; C12.950.419.473.585.950; C12.950.983.535.585.950; C16.131.260.940; C16.131.384.079.950; C16.131.939.316.096.875; C16.320.180.940; C16.320.290.078.950; C16.320.700.900.950; C19.391.119.096.875
C536370	Aniridia cerebellar ataxia mental deficiency (supp.)
C535970	Coloboma of optic nerve (supp.)
C537022	Keratitis, hereditary (supp.)
C537858	O’Donnell Pappas syndrome (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression	11
Tretinoin	affects cotreatment, increases expression, increases reaction, decreases expression, affects expression	7
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
bisphenol A	decreases expression, increases methylation, affects expression, affects reaction, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	4
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, decreases expression	4
Lead	decreases expression	4
methylmercuric chloride	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	3
decabromobiphenyl ether	affects cotreatment, decreases expression, increases expression	2
arsenite	affects binding, decreases reaction, increases methylation	2
perfluorooctanoic acid	decreases expression, increases activity	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, decreases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression	2
LDN 193189	increases expression, decreases reaction, increases reaction, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Atrazine	decreases expression, affects methylation, increases abundance	2
Paraquat	affects expression, affects reaction, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
propionaldehyde	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
decamethrin	affects cotreatment, decreases reaction, increases expression	1
bis(2,3,3,3-tetrachloropropyl) ether	affects cotreatment, increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
diethyl phosphate	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1

Cellosaurus cell lines

11 cell lines: 6 cancer cell line, 3 embryonic stem cell, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5E1	SEES3-1V human PAX6, clone1	Embryonic stem cell	Male
CVCL_A5E2	SEES3-1V human PAX6, clone2	Embryonic stem cell	Male
CVCL_A5E3	SEES3-1V human PAX6, clone3	Embryonic stem cell	Male
CVCL_A5TU	U-251MG PAX6-/- 2.10	Cancer cell line	Male
CVCL_A5TV	U-251MG PAX6-/- 2A.28	Cancer cell line	Male
CVCL_A5TW	U-251MG PAX6-/- 2A.3	Cancer cell line	Male
CVCL_B8M2	Abcam HCT 116 PAX6 KO	Cancer cell line	Male
CVCL_B9P9	Abcam A-549 PAX6 KO	Cancer cell line	Male
CVCL_D2GT	Abcam MCF-7 PAX6 KO	Cancer cell line	Female
CVCL_YK74	SDQLCHi010-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00121355	PHASE4	COMPLETED	Novofine Autocover Safety Needle Versus BD Safety Glide
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00162344	PHASE4	COMPLETED	A Study of Stress Heart Imaging in Patients With Diabetes at Risk for Coronary Disease.
NCT00177138	PHASE4	TERMINATED	Use of Campath for Induction and Maintenance Therapy in Pancreas After Kidney Transplantation
NCT00182494	PHASE4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00202618	PHASE4	UNKNOWN	Rationale and Design for Shiga Microalbuminuria Reduction Trial
NCT00209170	PHASE4	COMPLETED	Depression-Diabetes Mechanisms: Urban African Americans
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00212004	PHASE4	TERMINATED	Pioglitazone Protects Diabetes Mellitus (DM) Patients Against Re-Infarction (PPAR Study)
NCT00219440	PHASE4	COMPLETED	A Portion-controlled Diet Will Prevent Weight Gain in Diabetics Treated With ACTOS
NCT00225849	PHASE4	UNKNOWN	Japanese Primary Prevention Project With Aspirin
NCT00231894	PHASE4	COMPLETED	Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00235014	PHASE4	COMPLETED	A Study for Prevention of Kidney Disease in Diabetic Patients (BENEDICT)
NCT00236379	PHASE4	COMPLETED	A Study of the Effects of Risperidone and Olanzapine on Blood Glucose (Sugar) in Patients With Schizophrenia or Schizoaffective Disorder
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00264901	PHASE4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00274274	PHASE4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00282451	PHASE4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00282659	PHASE4	COMPLETED	The Use of Magnesium to Improve Blood Pressure, Cholesterol, and Glucose Control
NCT00287820	PHASE4	COMPLETED	Comparative Effects of Chronic Treatment With Olanzapine and Risperidone on Glucose and Lipid Metabolism
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00299169	PHASE4	TERMINATED	Randomized Trial Comparing N of 1 Trials to Standard Practice to Improve Adherence to Statins in Patients With Diabetes
NCT00301392	PHASE4	COMPLETED	Japan Prevention Trial of Diabetes by Pitavastatin in Patients With Impaired Glucose Tolerance (J-PREDICT)
NCT00306696	PHASE4	COMPLETED	Examining the Effect of Different Diuretics on Fluid Retention in Diabetics Treated With Rosiglitazone.
NCT00309465	PHASE4	COMPLETED	Perioperative Insulin Glargine Dosing Study