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O43316 (PAX4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 140. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Paired box protein Pax-4
Gene names
Name:PAX4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length350 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that binds to a common element in the glucagon, insulin and somatostatin promoters. Competes with PAX6 for this same promoter binding site. Isoform 2 appears to be a dominant negative form antagonizing PAX4 transcriptional activity.

Subcellular location

Nucleus.

Involvement in disease

Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.8

Diabetes mellitus, ketosis-prone (KPD) [MIM:612227]: An atypical form of diabetes mellitus characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Maturity-onset diabetes of the young 9 (MODY9) [MIM:612225]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9

Sequence similarities

Belongs to the paired homeobox family.

Contains 1 homeobox DNA-binding domain.

Contains 1 paired domain.

Sequence caution

The sequence AC073934 differs from that shown. Reason: According to the human genome assembly there is a stop codon in position 349.

Ontologies

Keywords
   Biological processDifferentiation
Transcription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDiabetes mellitus
Disease mutation
   DomainHomeobox
Paired box
   LigandDNA-binding
   Molecular functionDevelopmental protein
Repressor
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell differentiation

Inferred from electronic annotation. Source: UniProtKB-KW

circadian rhythm

Inferred from electronic annotation. Source: Ensembl

endocrine pancreas development

Traceable author statement. Source: Reactome

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

organ morphogenesis

Traceable author statement PubMed 9480859. Source: ProtInc

positive regulation of cell differentiation

Inferred from electronic annotation. Source: Ensembl

response to cAMP

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

retina development in camera-type eye

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentnucleoplasm

Traceable author statement. Source: Reactome

   Molecular_functionDNA binding

Traceable author statement PubMed 9480859. Source: ProtInc

double-stranded DNA binding

Inferred from electronic annotation. Source: Ensembl

sequence-specific DNA binding

Inferred from electronic annotation. Source: InterPro

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O43316-1)

Also known as: Pax4;

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 2 (identifier: O43316-2)

Also known as: Pax4V;

The sequence of this isoform differs from the canonical sequence as follows:
     239-257: Missing.
     258-350: QSPGSVPTAA...ATPTHFSHWP → AVPWQCAHSSPACPGTTGSLLLSAVLGNSTRKVSE
Isoform 3 (identifier: O43316-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-8: Missing.
     305-350: DCGSFLLPVI...ATPTHFSHWP → GHLPPQPNSL...PGCPLLYGLE

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 350350Paired box protein Pax-4
PRO_0000050180

Regions

Domain5 – 131127Paired
DNA binding170 – 22960Homeobox
Region278 – 35073Transcription repression

Natural variations

Alternative sequence1 – 88Missing in isoform 3.
VSP_036448
Alternative sequence239 – 25719Missing in isoform 2.
VSP_002359
Alternative sequence258 – 35093QSPGS…FSHWP → AVPWQCAHSSPACPGTTGSL LLSAVLGNSTRKVSE in isoform 2.
VSP_002360
Alternative sequence305 – 35046DCGSF…FSHWP → GHLPPQPNSLDSGLLCLPCP SSHCHLASLSGSQALLWPGC PLLYGLE in isoform 3.
VSP_036449
Natural variant391R → Q. Ref.9
Corresponds to variant rs115887120 [ dbSNP | Ensembl ].
VAR_054879
Natural variant451R → W Associated with PKD susceptbility. Ref.7
VAR_054880
Natural variant1291R → W in diabetes mellitus type 2. Ref.6
Corresponds to variant rs114202595 [ dbSNP | Ensembl ].
VAR_054881
Natural variant1411R → W Confers susceptibility to ketosis-prone diabetes mellitus. Ref.7
Corresponds to variant rs2233578 [ dbSNP | Ensembl ].
VAR_054882
Natural variant1721R → W in MODY9; the mutant sequence represses the activity of the insulin and glucagon promoters by only 35% compared to 50% and 57% respectively with wild-type sequence. Ref.9
VAR_054883
Natural variant1911R → C. Ref.9
Corresponds to variant rs114315130 [ dbSNP | Ensembl ].
VAR_054884
Natural variant2001R → H. Ref.9
Corresponds to variant rs2233580 [ dbSNP | Ensembl ].
VAR_054885
Natural variant2001R → S. Ref.9
Corresponds to variant rs3824004 [ dbSNP | Ensembl ].
VAR_054886
Isoform 3:
Natural variant3211H → P Associated with susceptibility to IDDM.
Corresponds to variant rs712701 [ dbSNP | Ensembl ].

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Pax4) [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: 2C2343AF16AEAAAC

FASTA35037,833
        10         20         30         40         50         60 
MHQDGISSMN QLGGLFVNGR PLPLDTRQQI VRLAVSGMRP CDISRILKVS NGCVSKILGR 

        70         80         90        100        110        120 
YYRTGVLEPK GIGGSKPRLA TPPVVARIAQ LKGECPALFA WEIQRQLCAE GLCTQDKTPS 

       130        140        150        160        170        180 
VSSINRVLRA LQEDQGLPCT RLRSPAVLAP AVLTPHSGSE TPRGTHPGTG HRNRTIFSPS 

       190        200        210        220        230        240 
QAEALEKEFQ RGQYPDSVAR GKLATATSLP EDTVRVWFSN RRAKWRRQEK LKWEMQLPGA 

       250        260        270        280        290        300 
SQGLTVPRVA PGIISAQQSP GSVPTAALPA LEPLGPSCYQ LCWATAPERC LSDTPPKACL 

       310        320        330        340        350 
KPCWDCGSFL LPVIAPSCVD VAWPCLDASL AHHLIGGAGK ATPTHFSHWP 

« Hide

Isoform 2 (Pax4V) [UniParc].

Checksum: 34658C1CBE7C81B5
Show »

FASTA27329,820
Isoform 3 [UniParc].

Checksum: D58E65CD918472DA
Show »

FASTA34337,061

References

« Hide 'large scale' references
[1]"Molecular cloning of mouse paired-box-containing gene (Pax-4) from an islet beta cell line and deduced sequence of human Pax-4."
Matsushita T., Yamaoka T., Otsuka S., Moritani M., Matsumoto T., Itakura M.
Biochem. Biophys. Res. Commun. 242:176-180(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Isolation and characterization of the human PAX4 gene."
Tao T., Wasson J., Bernal-Mizrachi E., Behn P.S., Chayen S., Duprat L., Meyer J., Glaser B., Permutt M.A.
Diabetes 47:1650-1653(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
Tissue: Placenta.
[3]"The DNA sequence of human chromosome 7."
Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Colon.
[5]"Expression of dominant negative form of PAX4 in human insulinoma."
Miyamoto T., Kakizawa T., Ichikawa K., Nishio S., Kajikawa S., Hashizume K.
Biochem. Biophys. Res. Commun. 282:34-40(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORM 2).
Tissue: Insulinoma.
[6]"A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese."
Shimajiri Y., Sanke T., Furuta H., Hanabusa T., Nakagawa T., Fujitani Y., Kajimoto Y., Takasu N., Nanjo K.
Diabetes 50:2864-2869(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT DIABETES MELLITUS TYPE 2 TRP-129.
[7]"PAX4 gene variations predispose to ketosis-prone diabetes."
Mauvais-Jarvis F., Smith S.B., Le May C., Leal S.M., Gautier J.-F., Molokhia M., Riveline J.-P., Rajan A.S., Kevorkian J.-P., Zhang S., Vexiau P., German M.S., Vaisse C.
Hum. Mol. Genet. 13:3151-3159(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS TRP-45 AND TRP-141, ASSOCIATION WITH SUSCEPTIBILITY TO KETOSIS-PRONE DIABETES.
[8]"Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity."
Biason-Lauber A., Boehm B., Lang-Muritano M., Gauthier B.R., Brun T., Wollheim C.B., Schoenle E.J.
Diabetologia 48:900-905(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT PRO-321 (ISOFORM 3), ASSOCIATION WITH SUSCEPTIBILITY TO IDDM.
[9]"PAX4 mutations in Thais with maturity onset diabetes of the young."
Plengvidhya N., Kooptiwut S., Songtawee N., Doi A., Furuta H., Nishi M., Nanjo K., Tantibhedhyangkul W., Boonyasrisawat W., Yenchitsomanus P.-T., Doria A., Banchuin N.
J. Clin. Endocrinol. Metab. 92:2821-2826(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT MODY9 TRP-172, VARIANTS GLN-39; CYS-191; HIS-200 AND SER-200, VARIANT PRO-321 (ISOFORM 3), CHARACTERIZATION OF VARIANT MODY9 TRP-172.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB008913 mRNA. Translation: BAA24506.1.
AF043978 mRNA. Translation: AAD02289.1.
AC073934 Genomic DNA. No translation available.
BC074761 mRNA. Translation: AAH74761.1.
CCDSCCDS5797.1. [O43316-4]
RefSeqNP_006184.2. NM_006193.2. [O43316-4]
UniGeneHs.129706.

3D structure databases

ProteinModelPortalO43316.
SMRO43316. Positions 7-135, 164-243.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING9606.ENSP00000339906.

Proteomic databases

PaxDbO43316.
PRIDEO43316.

Protocols and materials databases

DNASU5078.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000338516; ENSP00000344297; ENSG00000106331. [O43316-2]
ENST00000341640; ENSP00000339906; ENSG00000106331. [O43316-4]
GeneID5078.
KEGGhsa:5078.
UCSCuc003vmg.1. human. [O43316-1]
uc010lld.1. human. [O43316-4]

Organism-specific databases

CTD5078.
GeneCardsGC07M127250.
H-InvDBHIX0033508.
HGNCHGNC:8618. PAX4.
HPAHPA006806.
HPA007182.
MIM125853. phenotype.
167413. gene.
222100. phenotype.
612225. phenotype.
612227. phenotype.
neXtProtNX_O43316.
Orphanet552. MODY syndrome.
PharmGKBPA32958.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG309473.
HOGENOMHOG000230939.
HOVERGENHBG009115.
KOK08032.
OMAESLGPSC.
OrthoDBEOG783MVM.
PhylomeDBO43316.
TreeFamTF320146.

Enzyme and pathway databases

ReactomeREACT_111045. Developmental Biology.
SignaLinkO43316.

Gene expression databases

ArrayExpressO43316.
BgeeO43316.
CleanExHS_PAX4.
GenevestigatorO43316.

Family and domain databases

Gene3D1.10.10.10. 2 hits.
1.10.10.60. 1 hit.
InterProIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
IPR001523. Paired_dom.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamPF00046. Homeobox. 1 hit.
PF00292. PAX. 1 hit.
[Graphical view]
PRINTSPR00027. PAIREDBOX.
SMARTSM00389. HOX. 1 hit.
SM00351. PAX. 1 hit.
[Graphical view]
SUPFAMSSF46689. SSF46689. 2 hits.
PROSITEPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
PS00034. PAIRED_1. 1 hit.
PS51057. PAIRED_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiPAX4.
GenomeRNAi5078.
NextBio19588.
PROO43316.
SOURCESearch...

Entry information

Entry namePAX4_HUMAN
AccessionPrimary (citable) accession number: O43316
Secondary accession number(s): O95161, Q6B0H0
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: June 1, 1998
Last modified: July 9, 2014
This is version 140 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM