RFX6_HUMAN
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 03-AUG-2022, entry version 160.
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; Q7Z5V6-2: PPP1R32; NbExp=3; IntAct=EBI-746118, EBI-12000762;
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; 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}.
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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; Q8HWS3; -.
DR PeptideAtlas; Q8HWS3; -.
DR PRIDE; Q8HWS3; -.
DR ProteomicsDB; 70500; -.
DR Antibodypedia; 32535; 75 antibodies from 19 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 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; GSAPCMF; -.
DR OrthoDB; 346630at2759; -.
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; 13 hits in 1088 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 tissues.
DR Genevisible; Q8HWS3; HS.
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: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:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
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; -; 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; PTHR12619; 1.
DR Pfam; PF02257; RFX_DNA_binding; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS51526; RFX_DBD; 1.
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
