ID RFX6_HUMAN Reviewed; 928 AA. AC Q8HWS3; Q5T6B3; DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot. DT 15-JAN-2008, sequence version 2. DT 24-JAN-2024, entry version 168. DE RecName: Full=DNA-binding protein RFX6; DE AltName: Full=Regulatory factor X 6; DE AltName: Full=Regulatory factor X domain-containing protein 1; GN Name=RFX6; Synonyms=RFXDC1; 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 [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS LYS-6 AND ALA-688. RC TISSUE=Testis; 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 [4] RP IDENTIFICATION. RX PubMed=18673564; DOI=10.1186/1471-2148-8-226; RA Aftab S., Semenec L., Chu J.S.-C., Chen N.; RT "Identification and characterization of novel human tissue-specific RFX RT transcription factors."; RL BMC Evol. Biol. 8:226-226(2008). RN [5] RP FUNCTION, DNA-BINDING, TISSUE SPECIFICITY, VARIANTS MTCHRS GLN-181 AND RP PRO-217, AND CHARACTERIZATION OF VARIANTS MTCHRS GLN-181 AND PRO-217. RX PubMed=20148032; DOI=10.1038/nature08748; RA Smith S.B., Qu H.Q., Taleb N., Kishimoto N.Y., Scheel D.W., Lu Y., RA Patch A.M., Grabs R., Wang J., Lynn F.C., Miyatsuka T., Mitchell J., RA Seerke R., Desir J., Eijnden S.V., Abramowicz M., Kacet N., Weill J., RA Renard M.E., Gentile M., Hansen I., Dewar K., Hattersley A.T., Wang R., RA Wilson M.E., Johnson J.D., Polychronakos C., German M.S.; RT "Rfx6 directs islet formation and insulin production in mice and humans."; RL Nature 463:775-780(2010). RN [6] RP VARIANT MTCHRS GLY-506, CHARACTERIZATION OF VARIANT MTCHRS GLY-506, RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=25497100; DOI=10.1016/j.celrep.2014.11.010; RA Chandra V., Albagli-Curiel O., Hastoy B., Piccand J., Randriamampita C., RA Vaillant E., Cave H., Busiah K., Froguel P., Vaxillaire M., Rorsman P., RA Polak M., Scharfmann R.; RT "RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human RT beta cells."; RL Cell Rep. 9:2206-2218(2014). CC -!- FUNCTION: Transcription factor required to direct islet cell CC differentiation during endocrine pancreas development. Specifically CC required for the differentiation of 4 of the 5 islet cell types and for CC the production of insulin (PubMed:20148032, PubMed:25497100). Not CC required for pancreatic PP (polypeptide-producing) cells CC differentiation. Acts downstream of NEUROG3 and regulates the CC transcription factors involved in beta-cell maturation and function, CC thereby restricting the expression of the beta-cell differentiation and CC specification genes, and thus the beta-cell fate choice. Activates CC transcription by forming a heterodimer with RFX3 and binding to the X- CC box in the promoter of target genes (PubMed:20148032). Involved in CC glucose-stimulated insulin secretion by promoting insulin and L-type CC calcium channel gene transcription (PubMed:25497100). CC {ECO:0000269|PubMed:20148032, ECO:0000269|PubMed:25497100}. CC -!- SUBUNIT: Interacts with RFX3. {ECO:0000250|UniProtKB:Q8C7R7}. CC -!- INTERACTION: CC Q8HWS3; P21549: AGXT; NbExp=3; IntAct=EBI-746118, EBI-727098; CC Q8HWS3; Q8NEC5: CATSPER1; NbExp=6; IntAct=EBI-746118, EBI-744545; CC Q8HWS3; P33240: CSTF2; NbExp=3; IntAct=EBI-746118, EBI-711360; CC Q8HWS3; Q9NQL9: DMRT3; NbExp=3; IntAct=EBI-746118, EBI-9679045; CC Q8HWS3; Q86UW9: DTX2; NbExp=4; IntAct=EBI-746118, EBI-740376; CC Q8HWS3; Q9H596: DUSP21; NbExp=3; IntAct=EBI-746118, EBI-7357329; CC Q8HWS3; O43559: FRS3; NbExp=6; IntAct=EBI-746118, EBI-725515; CC Q8HWS3; A0A0S2Z4Q4: HGS; NbExp=3; IntAct=EBI-746118, EBI-16429135; CC Q8HWS3; O14964: HGS; NbExp=3; IntAct=EBI-746118, EBI-740220; CC Q8HWS3; Q7L273: KCTD9; NbExp=3; IntAct=EBI-746118, EBI-4397613; CC Q8HWS3; P56470: LGALS4; NbExp=3; IntAct=EBI-746118, EBI-720805; CC Q8HWS3; Q9Y316: MEMO1; NbExp=3; IntAct=EBI-746118, EBI-1104564; CC Q8HWS3; Q14511: NEDD9; NbExp=3; IntAct=EBI-746118, EBI-2108053; CC Q8HWS3; Q14511-2: NEDD9; NbExp=3; IntAct=EBI-746118, EBI-11746523; CC Q8HWS3; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-746118, EBI-11022007; CC Q8HWS3; Q494U1: PLEKHN1; NbExp=3; IntAct=EBI-746118, EBI-10241513; CC Q8HWS3; Q13131: PRKAA1; NbExp=3; IntAct=EBI-746118, EBI-1181405; CC Q8HWS3; P54646: PRKAA2; NbExp=3; IntAct=EBI-746118, EBI-1383852; CC Q8HWS3; P48378: RFX2; NbExp=4; IntAct=EBI-746118, EBI-746731; CC Q8HWS3; Q7Z5V6-2: SAXO4; NbExp=3; IntAct=EBI-746118, EBI-12000762; CC Q8HWS3; P14678-2: SNRPB; NbExp=6; IntAct=EBI-746118, EBI-372475; CC Q8HWS3; Q5TAL4: SNRPC; NbExp=3; IntAct=EBI-746118, EBI-10246938; CC Q8HWS3; O75177-5: SS18L1; NbExp=3; IntAct=EBI-746118, EBI-12035119; CC Q8HWS3; O75716: STK16; NbExp=3; IntAct=EBI-746118, EBI-749295; CC Q8HWS3; Q9BXF9: TEKT3; NbExp=3; IntAct=EBI-746118, EBI-8644516; CC Q8HWS3; Q8WW24: TEKT4; NbExp=3; IntAct=EBI-746118, EBI-750487; CC Q8HWS3; Q96A09: TENT5B; NbExp=3; IntAct=EBI-746118, EBI-752030; CC Q8HWS3; Q08117: TLE5; NbExp=3; IntAct=EBI-746118, EBI-717810; CC Q8HWS3; O75604: USP2; NbExp=3; IntAct=EBI-746118, EBI-743272; CC Q8HWS3; A5D8V6: VPS37C; NbExp=3; IntAct=EBI-746118, EBI-2559305; CC Q8HWS3; Q96E35: ZMYND19; NbExp=3; IntAct=EBI-746118, EBI-746595; CC Q8HWS3; A0A0S2Z5X4: ZNF688; NbExp=3; IntAct=EBI-746118, EBI-16429014; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25497100}. CC -!- TISSUE SPECIFICITY: Expressed in pancreas (PubMed:25497100). Expressed CC in pancreatic beta-cells (insulin-positive cells) and alpha-cells CC (glucagon-positive cells) (at protein level). Specifically expressed in CC pancreas, small intestine and colon (PubMed:20148032). Expressed in CC endocrine cells in the islets (PubMed:25497100). CC {ECO:0000269|PubMed:20148032, ECO:0000269|PubMed:25497100}. CC -!- DISEASE: Mitchell-Riley syndrome (MTCHRS) [MIM:615710]: A disorder CC characterized by neonatal diabetes, hypoplastic or annular pancreas, CC duodenal and jejunal atresia, and absent gallbladder. There is no CC dysmorphic features. {ECO:0000269|PubMed:20148032, CC ECO:0000269|PubMed:25497100}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the RFX family. {ECO:0000255|PROSITE- CC ProRule:PRU00858}. 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; AL355272; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48213.1; -; Genomic_DNA. DR EMBL; BC039248; AAH39248.1; -; mRNA. DR CCDS; CCDS5113.1; -. DR RefSeq; NP_775831.2; NM_173560.3. DR AlphaFoldDB; Q8HWS3; -. DR SMR; Q8HWS3; -. DR BioGRID; 128803; 43. DR IntAct; Q8HWS3; 43. DR MINT; Q8HWS3; -. DR STRING; 9606.ENSP00000332208; -. DR iPTMnet; Q8HWS3; -. DR PhosphoSitePlus; Q8HWS3; -. DR BioMuta; RFX6; -. DR DMDM; 166225159; -. DR MassIVE; Q8HWS3; -. DR PaxDb; 9606-ENSP00000332208; -. DR PeptideAtlas; Q8HWS3; -. DR ProteomicsDB; 70500; -. DR Antibodypedia; 32535; 84 antibodies from 20 providers. DR DNASU; 222546; -. DR Ensembl; ENST00000332958.3; ENSP00000332208.2; ENSG00000185002.10. DR GeneID; 222546; -. DR KEGG; hsa:222546; -. DR MANE-Select; ENST00000332958.3; ENSP00000332208.2; NM_173560.4; NP_775831.2. DR UCSC; uc003pxm.4; human. DR AGR; HGNC:21478; -. DR CTD; 222546; -. DR DisGeNET; 222546; -. DR GeneCards; RFX6; -. DR HGNC; HGNC:21478; RFX6. DR HPA; ENSG00000185002; Group enriched (adrenal gland, intestine, pancreas, stomach). DR MalaCards; RFX6; -. DR MIM; 612659; gene. DR MIM; 615710; phenotype. DR neXtProt; NX_Q8HWS3; -. DR OpenTargets; ENSG00000185002; -. DR Orphanet; 293864; Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome. DR PharmGKB; PA162401254; -. DR VEuPathDB; HostDB:ENSG00000185002; -. DR eggNOG; KOG3712; Eukaryota. DR GeneTree; ENSGT01050000244879; -. DR HOGENOM; CLU_013981_0_0_1; -. DR InParanoid; Q8HWS3; -. DR OMA; PGQMELS; -. DR OrthoDB; 2915941at2759; -. DR PhylomeDB; Q8HWS3; -. DR TreeFam; TF321340; -. DR PathwayCommons; Q8HWS3; -. DR Reactome; R-HSA-210745; Regulation of gene expression in beta cells. DR SignaLink; Q8HWS3; -. DR BioGRID-ORCS; 222546; 15 hits in 1168 CRISPR screens. DR GeneWiki; RFX6; -. DR GenomeRNAi; 222546; -. DR Pharos; Q8HWS3; Tbio. DR PRO; PR:Q8HWS3; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q8HWS3; Protein. DR Bgee; ENSG00000185002; Expressed in islet of Langerhans and 42 other cell types or tissues. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB. 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:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:NTNU_SB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0031018; P:endocrine pancreas development; IMP:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB. DR GO; GO:0003310; P:pancreatic A cell differentiation; ISS:UniProtKB. DR GO; GO:0003311; P:pancreatic D cell differentiation; ISS:UniProtKB. DR GO; GO:0090104; P:pancreatic epsilon cell differentiation; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB. DR GO; GO:0050796; P:regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0003309; P:type B pancreatic cell differentiation; ISS:UniProtKB. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR InterPro; IPR003150; DNA-bd_RFX. DR InterPro; IPR039779; RFX-like. DR InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR PANTHER; PTHR12619:SF28; DNA-BINDING PROTEIN RFX6; 1. DR PANTHER; PTHR12619; RFX TRANSCRIPTION FACTOR FAMILY; 1. DR Pfam; PF02257; RFX_DNA_binding; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS51526; RFX_DBD; 1. DR Genevisible; Q8HWS3; HS. PE 1: Evidence at protein level; KW Developmental protein; Diabetes mellitus; Differentiation; Disease variant; KW DNA-binding; Nucleus; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..928 FT /note="DNA-binding protein RFX6" FT /id="PRO_0000313721" FT DNA_BIND 124..199 FT /note="RFX-type winged-helix" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00858" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 50..98 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 82..98 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 6 FT /note="E -> K (in dbSNP:rs17853900)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_037709" FT VARIANT 17 FT /note="A -> E (in dbSNP:rs9489056)" FT /id="VAR_061768" FT VARIANT 181 FT /note="R -> Q (in MTCHRS; abolishes DNA-binding; FT dbSNP:rs267607013)" FT /evidence="ECO:0000269|PubMed:20148032" FT /id="VAR_062978" FT VARIANT 217 FT /note="S -> P (in MTCHRS; induces a slight reduction in FT DNA-binding; in a patient still alive at age 4.5 years; FT dbSNP:rs267607012)" FT /evidence="ECO:0000269|PubMed:20148032" FT /id="VAR_062979" FT VARIANT 506 FT /note="V -> G (in MTCHRS; inhibits the transactivation of FT the insulin and beta-cell L-type calcium channel genes)" FT /evidence="ECO:0000269|PubMed:25497100" FT /id="VAR_074215" FT VARIANT 688 FT /note="T -> A (in dbSNP:rs17857184)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_037710" FT VARIANT 743 FT /note="S -> N (in dbSNP:rs582803)" FT /id="VAR_037711" SQ SEQUENCE 928 AA; 102461 MW; 9BB5340736CFC903 CRC64; MAKVPELEDT FLQAQPAPQL SPGIQEDCCV QLLGKGLLVY PEETVYLAAE GQPGGEQGGG EKGEDPELPG AVKSEMHLNN GNFSSEEEDA DNHDSKTKAA DQYLSQKKTI TQIVKDKKKQ TQLTLQWLEE NYIVCEGVCL PRCILYAHYL DFCRKEKLEP ACAATFGKTI RQKFPLLTTR RLGTRGHSKY HYYGIGIKES SAYYHSVYSG KGLTRFSGSK LKNEGGFTRK YSLSSKTGTL LPEFPSAQHL VYQGCISKDK VDTLIMMYKT HCQCILDNAI NGNFEEIQHF LLHFWQGMPD HLLPLLENPV IIDIFCVCDS ILYKVLTDVL IPATMQEMPE SLLADIRNFA KNWEQWVVSS LENLPEALTD KKIPIVRRFV SSLKRQTSFL HLAQIARPAL FDQHVVNSMV SDIERVDLNS IGSQALLTIS GSTDTESGIY TEHDSITVFQ ELKDLLKKNA TVEAFIEWLD TVVEQRVIKT SKQNGRSLKK RAQDFLLKWS FFGARVMHNL TLNNASSFGS FHLIRMLLDE YILLAMETQF NNDKEQELQN LLDKYMKNSD ASKAAFTASP SSCFLANRNK GSMVSSDAVK NESHVETTYL PLPSSQPGGL GPALHQFPAG NTDNMPLTGQ MELSQIAGHL MTPPISPAMA SRGSVINQGP MAGRPPSVGP VLSAPSHCST YPEPIYPTLP QANHDFYSTS SNYQTVFRAQ PHSTSGLYPH HTEHGRCMAW TEQQLSRDFF SGSCAGSPYN SRPPSSYGPS LQAQDSHNMQ FLNTGSFNFL SNTGAASCQG ATLPPNSPNG YYGSNINYPE SHRLGSMVNQ HVSVISSIRS LPPYSDIHDP LNILDDSGRK QTSSFYTDTS SPVACRTPVL ASSLQTPIPS SSSQCMYGTS NQYPAQETLD SHGTSSREMV SSLPPINTVF MGTAAGGT //