PAX6

Paired box 6
PDB rendering based on 2cue.
Available structures PDB 2CUE, 6PAX
Identifiers
Symbols	PAX6; AN; AN2; D11S812E; MGC17209; MGDA; WAGR
External IDs	OMIM: 607108 MGI: 97490 HomoloGene: 1212 GeneCards: PAX6 Gene
Gene Ontology Molecular function • RNA polymerase II core promoter sequence-specific DNA binding • sequence-specific DNA binding RNA polymerase II transcription factor activity • DNA binding • sequence-specific DNA binding transcription factor activity • ubiquitin-protein ligase activity • protein binding • sequence-specific DNA binding • R-SMAD binding Cellular component • nuclear chromatin • nucleus • nucleolus • cytoplasm Biological process • blood vessel development • eye development • pancreatic A cell development • transcription, DNA-dependent • regulation of transcription, DNA-dependent • transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • multicellular organismal development • central nervous system development • visual perception • response to wounding • organ morphogenesis • positive regulation of gene expression • protein ubiquitination • cell differentiation • glucose homeostasis • positive regulation of transcription, DNA-dependent • neuron fate commitment • negative regulation of neurogenesis • iris morphogenesis • cornea development in camera-type eye Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5080	18508
Ensembl	ENSG00000007372	ENSMUSG00000027168
UniProt	P26367	Q3UTV5
RefSeq (mRNA)	NM_000280.3	NM_013627.4
RefSeq (protein)	NP_000271.1	NP_038655.1
Location (UCSC)	Chr 11: 31.81 – 31.84 Mb	Chr 2: 105.51 – 105.54 Mb
PubMed search	[1]	[2]

Paired box protein Pax-6 also known as aniridia type II protein (AN2) or oculorhombin is a protein that in humans is encoded by the PAX6 gene.^[1]

Function

PAX6 is a member of the Pax gene family. It acts as a "master control" gene for the development of eyes and other sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues.^{[citation needed]} However it has been recognized that a suite of genes is necessary for eye development, and therefore the term of "master control" gene may be a misnomer.^[2] This transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because heterozygous mutants produce a wide spectrum of ocular defects such as Aniridia in humans.^[3]

Species distribution

PAX6 protein function is highly conserved across bilaterian species. For instance, mouse PAX6 can trigger eye development in Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences.^[4]

Genomic organisation of the PAX6 locus varies considerably among species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites. The first work on genomic organisation was performed in quail, but the picture of the mouse locus is the most complete to date. This consists of 2 confirmed promoters (P0 and P1), 16 exons, and at least 6 enhancers. The 16 confirmed exons are numbered 0 through 13 with the additions of exon α located between exons 4 and 5, and the alternatively spliced exon 5a. Each promoter is associated with its own proximal exon (exon 0 for P0, exon 1 for P1) resulting in transcripts which are alternatively spliced in the 5’ un-translated region.

Of the four Drosophila Pax6 orthologues, it is thought that the eyeless (ey) and twin of eyeless (toy) gene products share functional homology with the vertebrate canonical Pax6 isoform, while the eyegone (eyg) and twin of eyegone (toe) gene products share functional homology with the vertebrate Pax6(5a) isoform. Eyeless and eyegone were named for their respective mutant phenotypes.

Isoforms

The vertebrate PAX6 locus encodes at least three different protein isoforms, these being the canonical PAX6, PAX6(5a), and PAX6(ΔPD). The canonical PAX6 protein contains an N-terminal paired domain, connected by a linker region to a paired-type homeodomain, and a proline/serine/threonine (P/S/T)-rich C-terminal domain. The paired domain and paired-type homeodomain each have DNA binding activities, while the P/S/T-rich domain possesses a transactivation function. PAX6(5a) is a product of the alternatively spliced exon 5a resulting in a 14 residue insertion in the paired domain which alters the specificity of this DNA binding activity. The nucleotide sequence corresponding to the linker region encodes a set of three alternative translation start codons from which the third PAX6 isoform originates. Collectively known as the PAX6(ΔPD) or pairedless isoforms, these three gene products all lack a paired domain. The pairedless proteins possess molecular weights of 43, 33, or 32kDa, depending on the particular start codon used. PAX6 transactivation function is attributed to the variable length C-terminal P/S/T-rich domain which stretches to 153 residues in human and mouse proteins.

References

1. ^ Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A, Hastie N, van Heyningen V (August 1992). "The human PAX6 gene is mutated in two patients with aniridia". Nat. Genet. 1 (5): 328–32. doi:10.1038/ng0892-328. PMID 1302030. 
2. ^ Fernald RD (2004). "Eyes: variety, development and evolution". Brain Behav. Evol. 64 (3): 141–7. doi:10.1159/000079743. PMID 15353906. 
3. ^ Davis LK, Meyer KJ, Rudd DS, Librant AL, Epping EA, Sheffield VC, Wassink TH (May 2008). "Pax6 3' deletion results in aniridia, autism and mental retardation". Hum. Genet. 123 (4): 371–8. doi:10.1007/s00439-008-0484-x. PMC 2719768. PMID 18322702. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2719768. 
4. ^ Gehring WJ, Ikeo K (September 1999). "Pax 6: mastering eye morphogenesis and eye evolution". Trends Genet. 15 (9): 371–7. PMID 10461206. 

See also

• Gillespie syndrome

Further reading

• Callaerts P, Halder G, Gehring WJ (1997). "PAX-6 in development and evolution.". Annu. Rev. Neurosci. 20 (1): 483–532. doi:10.1146/annurev.neuro.20.1.483. PMID 9056723. 
• Prosser J, van Heyningen V (1998). "PAX6 mutations reviewed.". Hum. Mutat. 11 (2): 93–108. doi:10.1002/(SICI)1098-1004(1998)11:2<93::AID-HUMU1>3.0.CO;2-M. PMID 9482572. 
• Hever AM, Williamson KA, van Heyningen V (2007). "Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.". Clin. Genet. 69 (6): 459–70. doi:10.1111/j.1399-0004.2006.00619.x. PMID 16712695. 
• Glaser T, Walton DS, Maas RL (1994). "Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene.". Nat. Genet. 2 (3): 232–9. doi:10.1038/ng1192-232. PMID 1345175. 
• Ton CC, Hirvonen H, Miwa H, et al. (1992). "Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region.". Cell 67 (6): 1059–74. doi:10.1016/0092-8674(91)90284-6. PMID 1684738. 
• O'Donnell FE, Pappas HR (1982). "Autosomal dominant foveal hypoplasia and presenile cataracts. A new syndrome.". Arch. Ophthalmol. 100 (2): 279–81. PMID 7065945. 
• Martha A, Strong LC, Ferrell RE, Saunders GF (1995). "Three novel aniridia mutations in the human PAX6 gene.". Hum. Mutat. 6 (1): 44–9. doi:10.1002/humu.1380060109. PMID 7550230. 
• Hanson I, Brown A, van Heyningen V (1995). "A new PAX6 mutation in familial aniridia.". J. Med. Genet. 32 (6): 488–9. doi:10.1136/jmg.32.6.488. PMC 1050493. PMID 7666404. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1050493. 
• Mirzayans F, Pearce WG, MacDonald IM, Walter MA (1995). "Mutation of the PAX6 gene in patients with autosomal dominant keratitis.". Am. J. Hum. Genet. 57 (3): 539–48. PMC 1801269. PMID 7668281. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1801269. 
• van Heyningen V, Little PF (1995). "Report of the fourth international workshop on human chromosome 11 mapping 1994.". Cytogenet. Cell Genet. 69 (3-4): 127–58. doi:10.1159/000133953. PMID 7698003. 
• Auffray C, Behar G, Bois F, et al. (1995). "[IMAGE: molecular integration of the analysis of the human genome and its expression]". C. R. Acad. Sci. III, Sci. Vie 318 (2): 263–72. PMID 7757816. 
• Martha A, Ferrell RE, Mintz-Hittner H, et al. (1994). "Paired box mutations in familial and sporadic aniridia predicts truncated aniridia proteins.". Am. J. Hum. Genet. 54 (5): 801–11. PMC 1918271. PMID 7909985. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1918271. 
• Glaser T, Jepeal L, Edwards JG, et al. (1994). "PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects.". Nat. Genet. 7 (4): 463–71. doi:10.1038/ng0894-463. PMID 7951315. 
• Epstein JA, Glaser T, Cai J, et al. (1994). "Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing.". Genes Dev. 8 (17): 2022–34. doi:10.1101/gad.8.17.2022. PMID 7958875. 
• Davis A, Cowell JK (1994). "Mutations in the PAX6 gene in patients with hereditary aniridia.". Hum. Mol. Genet. 2 (12): 2093–7. doi:10.1093/hmg/2.12.2093. PMID 8111379. 
• Hanson IM, Fletcher JM, Jordan T, et al. (1994). "Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly.". Nat. Genet. 6 (2): 168–73. doi:10.1038/ng0294-168. PMID 8162071. 
• Hanson IM, Seawright A, Hardman K, et al. (1993). "PAX6 mutations in aniridia.". Hum. Mol. Genet. 2 (7): 915–20. doi:10.1093/hmg/2.7.915. PMID 8364574. 
• Azuma N, Nishina S, Yanagisawa H, et al. (1996). "PAX6 missense mutation in isolated foveal hypoplasia.". Nat. Genet. 13 (2): 141–2. doi:10.1038/ng0696-141. PMID 8640214. 

External links

• MeSH PAX6+protein
• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
• GeneReviews/NCBI/NIH/UW entry on Aniridia
• OMIM entries on Aniridia