O43316 (PAX4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Paired box protein Pax-4

Gene names

Name:

PAX4

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	350 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Defects in PAX4 are a cause of noninsulin-dependent diabetes mellitus (NIDDM) [MIM:125853]; also known as diabetes mellitus type 2 or maturity-onset diabetes. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance. Genetic variations in PAX4 are associated with susceptibility to insulin-dependent diabetes mellitus (IDDM) [MIM:222100]. IDDM normally starts in childhood or adolescence and is caused by the body's own immune system which destroys the insulin-producing beta cells in the pancreas. Classical features are polydipsia, polyphagia and polyuria, due to hyperglycemia-induced osmotic diuresis. Ref.8 Defects in PAX4 are a cause of susceptibility to diabetes mellitus ketosis-prone (KPD) [MIM:612227]. KPD is 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. Defects in PAX4 are the cause of maturity-onset diabetes of the young type 9 (MODY9) [MIM:612225]. MODY is 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. 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 process	Differentiation Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Homeobox Paired box
Ligand	DNA-binding
Molecular function	Developmental protein Repressor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW endocrine pancreas development Traceable author statement. Source: Reactome organ morphogenesis Traceable author statement. Source: ProtInc transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleoplasm Traceable author statement. Source: Reactome
Molecular function	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 key	Position(s)	Length	Description	Graphical view	Feature identifier
	Natural variant	321	1	H → P Associated with susceptibility to IDDM. Corresponds to variant rs712701 [ dbSNP | Ensembl ].

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 350	350	Paired box protein Pax-4		PRO_0000050180
Regions
	Domain	5 – 131	127	Paired
	DNA binding	170 – 229	60	Homeobox
	Region	278 – 350	73	Transcription repression
Natural variations
	Alternative sequence	1 – 8	8	Missing in isoform 3.		VSP_036448
	Alternative sequence	239 – 257	19	Missing in isoform 2.		VSP_002359
	Alternative sequence	258 – 350	93	QSPGS…FSHWP → AVPWQCAHSSPACPGTTGSL LLSAVLGNSTRKVSE in isoform 2.		VSP_002360
	Alternative sequence	305 – 350	46	DCGSF…FSHWP → GHLPPQPNSLDSGLLCLPCP SSHCHLASLSGSQALLWPGC PLLYGLE in isoform 3.		VSP_036449
	Natural variant	39	1	R → Q. Ref.9		VAR_054879
	Natural variant	45	1	R → W Associated with PKD susceptbility. Ref.7		VAR_054880
	Natural variant	129	1	R → W in diabetes mellitus type 2. Ref.6		VAR_054881
	Natural variant	141	1	R → W Confers susceptibility to ketosis-prone diabetes mellitus. Ref.7		VAR_054882
	Natural variant	172	1	R → 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 variant	191	1	R → C. Ref.9		VAR_054884
	Natural variant	200	1	R → H. Ref.9		VAR_054885
	Natural variant	200	1	R → S. Ref.9		VAR_054886

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Pax4) [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 2C2343AF16AEAAAC	FASTA	350	37,833
	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
	Isoform 2 (Pax4V) [UniParc]. Checksum: 34658C1CBE7C81B5	FASTA	273	29,820
	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 LKWEMQLPAV 250 260 270 PWQCAHSSPA CPGTTGSLLL SAVLGNSTRK VSE
	Isoform 3 [UniParc]. Checksum: D58E65CD918472DA	FASTA	343	37,061
	10 20 30 40 50 60 MNQLGGLFVN GRPLPLDTRQ QIVRLAVSGM RPCDISRILK VSNGCVSKIL GRYYRTGVLE 70 80 90 100 110 120 PKGIGGSKPR LATPPVVARI AQLKGECPAL FAWEIQRQLC AEGLCTQDKT PSVSSINRVL 130 140 150 160 170 180 RALQEDQGLP CTRLRSPAVL APAVLTPHSG SETPRGTHPG TGHRNRTIFS PSQAEALEKE 190 200 210 220 230 240 FQRGQYPDSV ARGKLATATS LPEDTVRVWF SNRRAKWRRQ EKLKWEMQLP GASQGLTVPR 250 260 270 280 290 300 VAPGIISAQQ SPGSVPTAAL PALEPLGPSC YQLCWATAPE RCLSDTPPKA CLKPCWGHLP 310 320 330 340 PQPNSLDSGL LCLPCPSSHC HLASLSGSQA LLWPGCPLLY GLE

References

	« Hide 'large scale' referencesShow '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: 9439631] [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: 9753306] [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. , 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: 12853948] [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: 15489334] [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: 11263967] [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: 11723072] [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: 15509590] [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: 15834548] [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: 17426099] [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.
IPI	IPI00011955. IPI00218426. IPI00844339.
RefSeq	NP_006184.2. NM_006193.2.
UniGene	Hs.129706.
3D structure databases
ProteinModelPortal	O43316.
SMR	O43316. Positions 7-135, 164-233.
ModBase	Search...
Protein-protein interaction databases
STRING	O43316.
Proteomic databases
PRIDE	O43316.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000378740; ENSP00000368014; ENSG00000106331.
GeneID	5078.
KEGG	hsa:5078.
UCSC	uc003vmg.1. human.
Organism-specific databases
CTD	5078.
GeneCards	GC07M127250.
H-InvDB	HIX0033508.
HGNC	HGNC:8618. PAX4.
HPA	HPA006806. HPA007182.
MIM	125853. phenotype. 167413. gene. 222100. phenotype. 612225. phenotype. 612227. phenotype.
neXtProt	NX_O43316.
Orphanet	552. MODY syndrome.
PharmGKB	PA32958.
GenAtlas	Search...
Phylogenomic databases
GeneTree	ENSGT00600000084285.
HOGENOM	HBG714463.
HOVERGEN	HBG009115.
Enzyme and pathway databases
Reactome	REACT_111045. Developmental Biology.
Gene expression databases
ArrayExpress	O43316.
Bgee	O43316.
CleanEx	HS_PAX4.
Genevestigator	O43316.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR009057. Homeodomain-like. IPR012287. Homeodomain-rel. IPR001523. Paired_box_N. IPR011991. WHTH_trsnscrt_rep_DNA-bd. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit. G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 2 hits.
KO	K08032.
Pfam	PF00046. Homeobox. 1 hit. PF00292. PAX. 1 hit. [Graphical view]
PRINTS	PR00027. PAIREDBOX.
SMART	SM00389. HOX. 1 hit. SM00351. PAX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 2 hits.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. PS00034. PAIRED_1. 1 hit. PS51057. PAIRED_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	19588.
SOURCE	Search...

Entry information

Entry name

PAX4_HUMAN

Accession

Primary (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:	January 25, 2012
This is version 113 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.