ID PAX4_HUMAN Reviewed; 350 AA.
AC O43316; O95161; Q6B0H0;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 24-JAN-2024, entry version 202.
DE RecName: Full=Paired box protein Pax-4;
GN Name=PAX4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9439631; DOI=10.1006/bbrc.1997.7935;
RA Matsushita T., Yamaoka T., Otsuka S., Moritani M., Matsumoto T.,
RA Itakura M.;
RT "Molecular cloning of mouse paired-box-containing gene (Pax-4) from an
RT islet beta cell line and deduced sequence of human Pax-4.";
RL Biochem. Biophys. Res. Commun. 242:176-180(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Placenta;
RX PubMed=9753306; DOI=10.2337/diabetes.47.10.1650;
RA Tao T., Wasson J., Bernal-Mizrachi E., Behn P.S., Chayen S., Duprat L.,
RA Meyer J., Glaser B., Permutt M.A.;
RT "Isolation and characterization of the human PAX4 gene.";
RL Diabetes 47:1650-1653(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP ALTERNATIVE SPLICING (ISOFORM 2).
RC TISSUE=Insulinoma;
RX PubMed=11263967; DOI=10.1006/bbrc.2001.4552;
RA Miyamoto T., Kakizawa T., Ichikawa K., Nishio S., Kajikawa S.,
RA Hashizume K.;
RT "Expression of dominant negative form of PAX4 in human insulinoma.";
RL Biochem. Biophys. Res. Commun. 282:34-40(2001).
RN [6]
RP VARIANT T2D TRP-129.
RX PubMed=11723072; DOI=10.2337/diabetes.50.12.2864;
RA Shimajiri Y., Sanke T., Furuta H., Hanabusa T., Nakagawa T., Fujitani Y.,
RA Kajimoto Y., Takasu N., Nanjo K.;
RT "A missense mutation of Pax4 gene (R121W) is associated with type 2
RT diabetes in Japanese.";
RL Diabetes 50:2864-2869(2001).
RN [7]
RP INVOLVEMENT IN KPD, AND VARIANTS KPD TRP-45 AND TRP-141.
RX PubMed=15509590; DOI=10.1093/hmg/ddh341;
RA Mauvais-Jarvis F., Smith S.B., Le May C., Leal S.M., Gautier J.-F.,
RA Molokhia M., Riveline J.-P., Rajan A.S., Kevorkian J.-P., Zhang S.,
RA Vexiau P., German M.S., Vaisse C.;
RT "PAX4 gene variations predispose to ketosis-prone diabetes.";
RL Hum. Mol. Genet. 13:3151-3159(2004).
RN [8]
RP VARIANT PRO-321 (ISOFORM 3).
RX PubMed=15834548; DOI=10.1007/s00125-005-1723-5;
RA Biason-Lauber A., Boehm B., Lang-Muritano M., Gauthier B.R., Brun T.,
RA Wollheim C.B., Schoenle E.J.;
RT "Association of childhood type 1 diabetes mellitus with a variant of PAX4:
RT possible link to beta cell regenerative capacity.";
RL Diabetologia 48:900-905(2005).
RN [9]
RP VARIANT MODY9 TRP-172, VARIANTS GLN-39; CYS-191; HIS-200 AND SER-200,
RP VARIANT PRO-321 (ISOFORM 3), AND CHARACTERIZATION OF VARIANT MODY9 TRP-172.
RX PubMed=17426099; DOI=10.1210/jc.2006-1927;
RA Plengvidhya N., Kooptiwut S., Songtawee N., Doi A., Furuta H., Nishi M.,
RA Nanjo K., Tantibhedhyangkul W., Boonyasrisawat W., Yenchitsomanus P.-T.,
RA Doria A., Banchuin N.;
RT "PAX4 mutations in Thais with maturity onset diabetes of the young.";
RL J. Clin. Endocrinol. Metab. 92:2821-2826(2007).
CC -!- FUNCTION: Plays an important role in the differentiation and
CC development of pancreatic islet beta cells. Transcriptional repressor
CC that binds to a common element in the glucagon, insulin and
CC somatostatin promoters. Competes with PAX6 for this same promoter
CC binding site. Isoform 2 appears to be a dominant negative form
CC antagonizing PAX4 transcriptional activity.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Pax4;
CC IsoId=O43316-1; Sequence=Displayed;
CC Name=2; Synonyms=Pax4V;
CC IsoId=O43316-2; Sequence=VSP_002359, VSP_002360;
CC Name=3;
CC IsoId=O43316-4; Sequence=VSP_036448, VSP_036449;
CC -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial
CC disorder of glucose homeostasis caused by a lack of sensitivity to the
CC body's own insulin. Affected individuals usually have an obese body
CC habitus and manifestations of a metabolic syndrome characterized by
CC diabetes, insulin resistance, hypertension and hypertriglyceridemia.
CC The disease results in long-term complications that affect the eyes,
CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:11723072}.
CC Note=Disease susceptibility may be associated with variants affecting
CC the gene represented in this entry.
CC -!- DISEASE: Diabetes mellitus, ketosis-prone (KPD) [MIM:612227]: An
CC atypical form of diabetes mellitus characterized by an acute initial
CC presentation with severe hyperglycemia and ketosis, as seen in classic
CC type 1 diabetes, but after initiation of insulin therapy, prolonged
CC remission is often possible with cessation of insulin therapy and
CC maintenance of appropriate metabolic control. Metabolic studies show a
CC markedly blunted insulin secretory response to glucose, partially
CC reversible with the improvement of blood glucose control. Variable
CC levels of insulin resistance are observed, especially in obese
CC patients. Pancreatic beta-cell autoimmunity is a rare finding.
CC {ECO:0000269|PubMed:15509590}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Maturity-onset diabetes of the young 9 (MODY9) [MIM:612225]: A
CC form of diabetes that is characterized by an autosomal dominant mode of
CC inheritance, onset in childhood or early adulthood (usually before 25
CC years of age), a primary defect in insulin secretion and frequent
CC insulin-independence at the beginning of the disease.
CC {ECO:0000269|PubMed:17426099}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the paired homeobox family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AC073934; Type=Miscellaneous discrepancy; Note=According to the human genome assembly there is a stop codon in position 349.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB008913; BAA24506.1; -; mRNA.
DR EMBL; AF043978; AAD02289.1; -; mRNA.
DR EMBL; AC073934; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC074761; AAH74761.1; -; mRNA.
DR RefSeq; NP_006184.2; NM_006193.2.
DR AlphaFoldDB; O43316; -.
DR SMR; O43316; -.
DR BioGRID; 111112; 17.
DR IntAct; O43316; 2.
DR STRING; 9606.ENSP00000368014; -.
DR GlyGen; O43316; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O43316; -.
DR PhosphoSitePlus; O43316; -.
DR BioMuta; PAX4; -.
DR MassIVE; O43316; -.
DR PaxDb; 9606-ENSP00000339906; -.
DR PeptideAtlas; O43316; -.
DR ProteomicsDB; 48895; -. [O43316-1]
DR ProteomicsDB; 48897; -. [O43316-4]
DR Antibodypedia; 1766; 367 antibodies from 36 providers.
DR DNASU; 5078; -.
DR Ensembl; ENST00000341640.6; ENSP00000339906.2; ENSG00000106331.19. [O43316-4]
DR UCSC; uc010lld.1; human. [O43316-1]
DR AGR; HGNC:8618; -.
DR GeneCards; PAX4; -.
DR GeneReviews; PAX4; -.
DR HGNC; HGNC:8618; PAX4.
DR HPA; ENSG00000106331; Not detected.
DR MalaCards; PAX4; -.
DR MIM; 125853; phenotype.
DR MIM; 167413; gene.
DR MIM; 612225; phenotype.
DR MIM; 612227; phenotype.
DR neXtProt; NX_O43316; -.
DR OpenTargets; ENSG00000106331; -.
DR Orphanet; 552; MODY.
DR PharmGKB; PA32958; -.
DR VEuPathDB; HostDB:ENSG00000106331; -.
DR eggNOG; KOG0849; Eukaryota.
DR GeneTree; ENSGT00940000161709; -.
DR HOGENOM; CLU_019281_1_2_1; -.
DR InParanoid; O43316; -.
DR PhylomeDB; O43316; -.
DR TreeFam; TF320146; -.
DR PathwayCommons; O43316; -.
DR Reactome; R-HSA-210746; Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
DR SignaLink; O43316; -.
DR BioGRID-ORCS; 5078; 8 hits in 1164 CRISPR screens.
DR ChiTaRS; PAX4; human.
DR GeneWiki; PAX4; -.
DR GenomeRNAi; 5078; -.
DR Pharos; O43316; Tbio.
DR PRO; PR:O43316; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O43316; Protein.
DR Bgee; ENSG00000106331; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 20 other cell types or tissues.
DR ExpressionAtlas; O43316; baseline and differential.
DR Genevisible; O43316; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003677; F:DNA binding; TAS:ProtInc.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0048856; P:anatomical structure development; IBA:GO_Central.
DR GO; GO:0009887; P:animal organ morphogenesis; TAS:ProtInc.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR CDD; cd00086; homeodomain; 1.
DR Gene3D; 1.10.10.60; Homeodomain-like; 1.
DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 2.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR043182; PAIRED_DNA-bd_dom.
DR InterPro; IPR001523; Paired_dom.
DR InterPro; IPR043565; PAX_fam.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR PANTHER; PTHR45636:SF8; PAIRED BOX PROTEIN PAX-4; 1.
DR PANTHER; PTHR45636; PAIRED BOX PROTEIN PAX-6-RELATED-RELATED; 1.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF00292; PAX; 1.
DR PRINTS; PR00027; PAIREDBOX.
DR SMART; SM00389; HOX; 1.
DR SMART; SM00351; PAX; 1.
DR SUPFAM; SSF46689; Homeodomain-like; 2.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
DR PROSITE; PS00034; PAIRED_1; 1.
DR PROSITE; PS51057; PAIRED_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Developmental protein; Diabetes mellitus;
KW Differentiation; Disease variant; DNA-binding; Homeobox; Nucleus;
KW Paired box; Reference proteome; Repressor; Transcription;
KW Transcription regulation.
FT CHAIN 1..350
FT /note="Paired box protein Pax-4"
FT /id="PRO_0000050180"
FT DNA_BIND 5..131
FT /note="Paired"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00381"
FT DNA_BIND 170..229
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 8..64
FT /note="PAI subdomain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00381"
FT REGION 83..131
FT /note="RED subdomain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00381"
FT REGION 153..172
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 278..350
FT /note="Transcription repression"
FT COMPBIAS 158..172
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..8
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9753306"
FT /id="VSP_036448"
FT VAR_SEQ 239..257
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_002359"
FT VAR_SEQ 258..350
FT /note="QSPGSVPTAALPALEPLGPSCYQLCWATAPERCLSDTPPKACLKPCWDCGSF
FT LLPVIAPSCVDVAWPCLDASLAHHLIGGAGKATPTHFSHWP -> AVPWQCAHSSPACP
FT GTTGSLLLSAVLGNSTRKVSE (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_002360"
FT VAR_SEQ 305..350
FT /note="DCGSFLLPVIAPSCVDVAWPCLDASLAHHLIGGAGKATPTHFSHWP -> GH
FT LPPQPNSLDSGLLCLPCPSSHCHLASLSGSQALLWPGCPLLYGLE (in isoform
FT 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9753306"
FT /id="VSP_036449"
FT VARIANT 39
FT /note="R -> Q (in dbSNP:rs115887120)"
FT /evidence="ECO:0000269|PubMed:17426099"
FT /id="VAR_054879"
FT VARIANT 45
FT /note="R -> W (in KPD; uncertain significance;
FT dbSNP:rs35155575)"
FT /evidence="ECO:0000269|PubMed:15509590"
FT /id="VAR_054880"
FT VARIANT 129
FT /note="R -> W (in T2D; uncertain significance;
FT dbSNP:rs114202595)"
FT /evidence="ECO:0000269|PubMed:11723072"
FT /id="VAR_054881"
FT VARIANT 141
FT /note="R -> W (in KPD; uncertain significance;
FT dbSNP:rs2233578)"
FT /evidence="ECO:0000269|PubMed:15509590"
FT /id="VAR_054882"
FT VARIANT 172
FT /note="R -> W (in MODY9; the mutant sequence represses the
FT activity of the insulin and glucagon promoters by only 35%
FT compared to 50% and 57% respectively with wild-type
FT sequence)"
FT /evidence="ECO:0000269|PubMed:17426099"
FT /id="VAR_054883"
FT VARIANT 191
FT /note="R -> C (in dbSNP:rs114315130)"
FT /evidence="ECO:0000269|PubMed:17426099"
FT /id="VAR_054884"
FT VARIANT 200
FT /note="R -> H (in dbSNP:rs2233580)"
FT /evidence="ECO:0000269|PubMed:17426099"
FT /id="VAR_054885"
FT VARIANT 200
FT /note="R -> S (in dbSNP:rs3824004)"
FT /evidence="ECO:0000269|PubMed:17426099"
FT /id="VAR_054886"
FT VARIANT O43316-4:321
FT /note="H -> P (in dbSNP:rs712701)"
FT /evidence="ECO:0000269|PubMed:15834548,
FT ECO:0000269|PubMed:17426099"
FT /id="VAR_082834"
SQ SEQUENCE 350 AA; 37833 MW; 2C2343AF16AEAAAC CRC64;
MHQDGISSMN QLGGLFVNGR PLPLDTRQQI VRLAVSGMRP CDISRILKVS NGCVSKILGR
YYRTGVLEPK GIGGSKPRLA TPPVVARIAQ LKGECPALFA WEIQRQLCAE GLCTQDKTPS
VSSINRVLRA LQEDQGLPCT RLRSPAVLAP AVLTPHSGSE TPRGTHPGTG HRNRTIFSPS
QAEALEKEFQ RGQYPDSVAR GKLATATSLP EDTVRVWFSN RRAKWRRQEK LKWEMQLPGA
SQGLTVPRVA PGIISAQQSP GSVPTAALPA LEPLGPSCYQ LCWATAPERC LSDTPPKACL
KPCWDCGSFL LPVIAPSCVD VAWPCLDASL AHHLIGGAGK ATPTHFSHWP
//
