Reviewed, UniProtKB/Swiss-Prot P26367 (PAX6_HUMAN)

Names and origin

Protein names

Recommended name:
    Paired box protein Pax-6
Alternative name(s):
    Oculorhombin
    Aniridia type II protein

Gene names

Name:	PAX6
Synonyms:	AN2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	422 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

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 By similarity. 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 By similarity. Isoform 5a appears to function as a molecular switch that specifies target genes.
Subcellular location	Nucleus.
Tissue specificity	Fetal eye, brain, spinal cord and olfactory epithelium. Isoform 5a is less abundant than the PAX6 shorter form.
Developmental stage	Expressed in the developing eye and brain.
Involvement in disease	Defects in PAX6 are the cause of aniridia type II (AN2) [MIM:106210]. AN2 is a bilateral panocular disorder characterized by complete or partial absence of the iris, absence of the fovea and malformations of the lens and anterior chamber. Severe age-related corneal degeneration is a frequent complication which contributes to a poor visual prognostis in aniridia. About one third of the cases are sporadic, and two thirds are familial, with autosomal dominant inheritance and high penetrance. Nearly one third of sporadic AN patients develop Wilms tumor in association with genitourinary anomalies and mental retardation (WAGR syndrome) as a consequence of heterozygous (sub)microscopic deletions of chromosome 11p13. Defects in PAX6 are a cause of Peters anomaly [MIM:604229]. Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea. Defects in PAX6 are a cause of ectopia pupillae [MIM:129750]. It is a congenital eye malformation in which the pupils are displaced from their normal central position. Defects in PAX6 are a cause of foveal hypoplasia [MIM:136520]. Foveal hypoplasia can be isolated or associated with presenile cataract. Inheritance is autosomal dominant. Defects in PAX6 are a cause of autosomal dominant keratitis [MIM:148190]. It is an eye disorder characterized by corneal opacification and vascularization, and by foveal hypoplasia. Defects in PAX6 are a cause of ocular coloboma [MIM:120200]; also known as uveoretinal coloboma or coloboma of iris, choroid and retina. 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). Severe colobomatous malformations may cause as much as 10% of the childhood blindness. The clinical presentation of ocular coloboma is variable. Some individuals may present with minimal defects in the anterior iris leaf without other ocular defects. More complex malformations create a combination of iris, uveoretinal and/or optic nerve defects without or with microphthalmia or even anophthalmia. Defects in PAX6 are a cause of coloboma of optic nerve [MIM:120430]. Defects in PAX6 are a cause of bilateral optic nerve hypoplasia [MIM:165550]; also known as bilateral optic nerve aplasia. Inheritance is autosomal dominant.
Sequence similarities	Belongs to the paired homeobox family. Contains 1 homeobox DNA-binding domain. Contains 1 paired domain.

Ontologies

Keywords
Biological process	Differentiation Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Homeobox Paired box
Ligand	DNA-binding
Molecular function	Developmental protein Repressor
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW central nervous system development Traceable author statement. Source: ProtInc eye development Traceable author statement. Source: ProtInc organ morphogenesis Ref.19 Traceable author statement. Source: ProtInc regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: InterPro visual perception Ref.19 Traceable author statement. Source: ProtInc
Cellular component	nucleus Inferred from electronic annotation. Source: InterPro
Molecular function	protein binding Inferred from physical interaction. Source: IntAct sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro transcription factor activity Ref.19 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Dynll1	P63168	2	EBI-747278,EBI-349121	From a different organism.
HOMER3	Q9NSC5	2	EBI-747278,EBI-748420
TRIM11	Q96F44	2	EBI-747278,EBI-851809

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P26367-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 5a (identifier: P26367-2)

Also known as: Pax6-5a;

The sequence of this isoform differs from the canonical sequence as follows:
     47-47: Q → QTHADAKVQVLDNQN

Isoform 3 (identifier: P26367-3)

Also known as: Pax6-5A,6*;

The sequence of this isoform is not available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 422

422

Paired box protein Pax-6

PRO_0000050185

Regions

Domain

4 – 130

127

Paired

DNA binding

210 – 269

60

Homeobox

Compositional bias

131 – 209

79

Gln/Gly-rich

Compositional bias

279 – 422

144

Pro/Ser/Thr-rich

Natural variations

Alternative sequence

47

1

Q → QTHADAKVQVLDNQN in isoform 5a.

VSP_002366

Natural variant

17

1

N → S in AN2.

VAR_003808

Natural variant

18

1

G → W in AN2 and Peters anomaly.

VAR_003809

Natural variant

22 – 26

5

Missing in AN2; sporadic form.

VAR_008693

Natural variant

26

1

R → G in Peters anomaly.

VAR_003810

Natural variant

29

1

I → S in AN2; sporadic form.

VAR_008694

Natural variant

29

1

I → V in AN2.

VAR_003811

Natural variant

33

1

A → P in AN2; sporadic form.

VAR_008695

Natural variant

37 – 39

3

Missing in AN2; sporadic form.

VAR_008696

Natural variant

42

1

I → S in AN2; mild.

VAR_008697

Natural variant

43

1

S → P in AN2; sporadic form.

VAR_008698

Natural variant

44

1

R → Q in AN2.

VAR_003812

Natural variant

53

1

V → D in Peters anomaly, congenital cataract and foveal hypoplasia; Japanese pedigrees.

VAR_008700

Natural variant

53

1

V → L in AN2; mild.

VAR_008699

Natural variant

63

1

T → P in AN2; mild.

VAR_008701

Natural variant

64

1

G → V in foveal hypoplasia; associated with presenile cataract syndrome.

VAR_008702

Natural variant

68

1

P → S in morning glory disk anomaly; significant impairment of transcriptional activation ability.

VAR_017540

Natural variant

79

1

A → E in AN2; mild.

VAR_008703

Natural variant

87

1

I → R in AN2; loss of activity.

VAR_003813

Natural variant

118

1

P → R in nystagmus associated with a variant form of aniridia.

VAR_015065

Natural variant

119

1

S → R in AN2; sporadic form.

VAR_008704

Natural variant

125

1

R → C in foveal hypoplasia; isolated.

VAR_017541

Natural variant

126

1

V → D in ectopia pupillae.

VAR_008705

Natural variant

128

1

R → C in foveal hypoplasia; isolated.

VAR_003814

Natural variant

178

1

Q → H in AN2.

VAR_003815

Natural variant

208

1

R → Q in AN2; mild.

VAR_008706

Natural variant

208

1

R → W in AN2.

VAR_003816

Natural variant

258

1

F → S in ocular coloboma; significant impairment of transcriptional activation ability.

VAR_017542

Natural variant

292

1

S → I in bilateral optic nerve hypoplasia; significant impairment of transcriptional activation ability.

VAR_017543

Natural variant

353

1

S → A in AN2; familial form.

VAR_008707

Natural variant

363

1

S → P in Peters anomaly.

VAR_017544

Natural variant

375

1

P → Q in AN2; reduced DNA binding ability.

VAR_015066

Natural variant

378

1

Q → R in optic nerve aplasia.

VAR_017545

Natural variant

381

1

M → V in bilateral optic nerve hypoplasia.

VAR_017546

Natural variant

391

1

T → A in bilateral optic nerve aplasia.

VAR_017547

Natural variant

422

1

Q → R in AN2 and ocular anterior segment anomalies; loss of DNA binding ability.

VAR_008708

Experimental info

Sequence conflict

317

1

R → L in AAA59963 and AAA59962. Ref.1

Sequence conflict

369

1

Y → C in CAE45868. Ref.4

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

422

Helix Strand Turn

Details...

Beta strand

6 – 8

3

Beta strand

14 – 16

3

Helix

23 – 34

12

Helix

39 – 46

8

Helix

50 – 63

14

Beta strand

77 – 79

3

Helix

81 – 93

13

Helix

99 – 108

10

Turn

114 – 116

3

Helix

120 – 133

14

Helix

219 – 229

11

Helix

237 – 246

10

Helix

251 – 275

25

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 15, 1999. Version 2. Checksum: C33CDD2C1B13C397	FASTA	422	46,683
	10 20 30 40 50 60 MQNSHSGVNQ LGGVFVNGRP LPDSTRQKIV ELAHSGARPC DISRILQVSN GCVSKILGRY 70 80 90 100 110 120 YETGSIRPRA IGGSKPRVAT PEVVSKIAQY KRECPSIFAW EIRDRLLSEG VCTNDNIPSV 130 140 150 160 170 180 SSINRVLRNL ASEKQQMGAD GMYDKLRMLN GQTGSWGTRP GWYPGTSVPG QPTQDGCQQQ 190 200 210 220 230 240 EGGGENTNSI SSNGEDSDEA QMRLQLKRKL QRNRTSFTQE QIEALEKEFE RTHYPDVFAR 250 260 270 280 290 300 ERLAAKIDLP EARIQVWFSN RRAKWRREEK LRNQRRQASN TPSHIPISSS FSTSVYQPIP 310 320 330 340 350 360 QPTTPVSSFT SGSMLGRTDT ALTNTYSALP PMPSFTMANN LPMQPPVPSQ TSSYSCMLPT 370 380 390 400 410 420 SPSVNGRSYD TYTPPHMQTH MNSQPMGTSG TTSTGLISPG VSVPVQVPGS EPDMSQYWPR LQ
	Isoform 5a (Pax6-5a) [UniParc]. Checksum: 74926827347A20B5		436	48,218
	10 20 30 40 50 60 MQNSHSGVNQ LGGVFVNGRP LPDSTRQKIV ELAHSGARPC DISRILQTHA DAKVQVLDNQ 70 80 90 100 110 120 NVSNGCVSKI LGRYYETGSI RPRAIGGSKP RVATPEVVSK IAQYKRECPS IFAWEIRDRL 130 140 150 160 170 180 LSEGVCTNDN IPSVSSINRV LRNLASEKQQ MGADGMYDKL RMLNGQTGSW GTRPGWYPGT 190 200 210 220 230 240 SVPGQPTQDG CQQQEGGGEN TNSISSNGED SDEAQMRLQL KRKLQRNRTS FTQEQIEALE 250 260 270 280 290 300 KEFERTHYPD VFARERLAAK IDLPEARIQV WFSNRRAKWR REEKLRNQRR QASNTPSHIP 310 320 330 340 350 360 ISSSFSTSVY QPIPQPTTPV SSFTSGSMLG RTDTALTNTY SALPPMPSFT MANNLPMQPP 370 380 390 400 410 420 VPSQTSSYSC MLPTSPSVNG RSYDTYTPPH MQTHMNSQPM GTSGTTSTGL ISPGVSVPVQ 430 VPGSEPDMSQ YWPRLQ
	Isoform 3 (Pax6-5A,6*) (Sequence not available).		–	–

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region." Ton C.C.T., Hirvonen H., Miwa H., Weil M.M., Monaghan P., Jordan T., van Heyningen V., Hastie N.D., Meijers-Heijboer H., Drechsler M., Royer-Pokora B., Collins F.S., Swaroop A., Strong L.C., Saunders G.F. Cell 67:1059-1074(1991) [PubMed: 1684738] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene." Glaser T., Walton D.S., Maas R.L. Nat. Genet. 2:232-239(1992) [PubMed: 1345175] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	Liu J., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE (ISOFORM PAX6).
[4]	The German cDNA consortium Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5A). Tissue: Cerebellum.
[5]	Wilkinson J. Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 5A).
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Lung.
[7]	"Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing." Epstein J.A., Glaser T., Cai J., Jepeal L., Walton D.S., Maas R.L. Genes Dev. 8:2022-2034(1994) [PubMed: 7958875] [Abstract] Cited for: ALTERNATIVE SPLICING, DNA-BINDING.
[8]	"Crystal structure of the human Pax-6 paired domain-DNA complex reveals specific roles for the linker region and carboxyl-terminal subdomain in DNA binding." Xu H.E., Rould M.A., Xu W., Epstein J.A., Maas R.L., Pabo C.O. Genes Dev. 13:1263-1275(1999) [PubMed: 10346815] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 4-136.
[9]	"PAX6 mutations reviewed." Prosser J., van Heyningen V. Hum. Mutat. 11:93-108(1998) [PubMed: 9482572] [Abstract] Cited for: REVIEW ON VARIANTS.
[10]	"Solution structure of the homeobox domain of the human paired box protein PAX-6." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 211-277.
[11]	"PAX6 mutations in aniridia." Hanson I.M., Seawright A., Hardman K., Hodgson S., Zaletayev D., Fekete G., van Heyningen V. Hum. Mol. Genet. 2:915-920(1993) [PubMed: 8364574] [Abstract] Cited for: VARIANT AN2 TRP-208.
[12]	"Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly." Hanson I.M., Fletcher J.M., Jordan T., Brown A., Taylor D., Adams R.J., Punnet H.H., van Heyningen V. Nat. Genet. 6:168-173(1994) [PubMed: 8162071] [Abstract] Cited for: VARIANT PETERS ANOMALY GLY-26.
[13]	"PAX6 missense mutation in isolated foveal hypoplasia." Azuma N., Nishina S., Yanagisawa H., Okuyama T., Yamada M. Nat. Genet. 13:141-142(1996) [PubMed: 8640214] [Abstract] Cited for: VARIANTS FOVEAL HYPOPLASIA CYS-125 AND CYS-128.
[14]	"Functional analysis of paired box missense mutations in the PAX6 gene." Tang H.K., Chao L.-Y., Saunders G.F. Hum. Mol. Genet. 6:381-386(1997) [PubMed: 9147640] [Abstract] Cited for: VARIANT AN2 ARG-87, VARIANT GLY-26.
[15]	"Combined SSCP/heteroduplex analysis in the screening for PAX6 mutations." Axton R., Hanson I.M., Love J., Seawright A., Prosser J., van Heyningen V. Mol. Cell. Probes 11:287-292(1997) [PubMed: 9281415] [Abstract] Cited for: VARIANT AN2 22-PRO--ARG-26 DEL.
[16]	"Ten novel mutations found in Aniridia." Wolf M.T.F., Lorenz B., Winterpacht A., Drechsler M., Schumacher V., Royer-Pokora B., Blankenagel A., Zabel B., Wildhardt G. Hum. Mutat. 12:304-313(1998) [PubMed: 9792406] [Abstract] Cited for: VARIANT AN2 TRP-18.
[17]	"Missense mutation at the C-terminus of the PAX6 gene in ocular anterior segment anomalies." Azuma N., Yamada M. Invest. Ophthalmol. Vis. Sci. 39:828-830(1998) [PubMed: 9538891] [Abstract] Cited for: VARIANT EYE MALFORMATIONS ARG-422.
[18]	"Missense mutations in the PAX6 gene in aniridia." Azuma N., Hotta Y., Tanaka H., Yamada M. Invest. Ophthalmol. Vis. Sci. 39:2524-2528(1998) [PubMed: 9856761] [Abstract] Cited for: VARIANTS AN2 SER-17; VAL-29; GLN-44 AND HIS-178.
[19]	"Missense mutation in the alternative splice region of the PAX6 gene in eye anomalie