Reviewed, UniProtKB/Swiss-Prot O14896 (IRF6_HUMAN)

Names and origin

Protein names

Recommended name:
    Interferon regulatory factor 6
      Short name=IRF-6

Gene names

Name:

IRF6

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Probable DNA-binding transcriptional activator. Key determinant of the keratinocyte proliferation-differentiation switch involved in appropriate epidermal development By similarity. Plays a role in regulating mammary epithelial cell proliferation By similarity.
Subunit structure	Interacts with SERPINB5. Ref.4
Subcellular location	Nucleus Potential. Cytoplasm. Note: Translocates to nucleus in response to an activating signal By similarity.
Tissue specificity	Expressed in normal mammary epithelial cells. Expression is reduced or absent in breast carcinomas. Ref.4
Post-translational modification	Phosphorylated. Phosphorylation status depends on the cell cycle and is a signal for ubiquitination and proteasome-mediated degradation. Ref.4 Ref.5
Involvement in disease	Defects in IRF6 are a cause of van der Woude syndrome (VWS) [MIM:119300]; also known as lip-pit syndrome (LPS). It is an autosomal dominant developmental disorder characterized by lower lip pits, cleft lip and/or cleft palate. Penetrance is incomplete. Van der Woude and popliteal pterygium syndrome are allelic disorders. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Defects in IRF6 are the cause of popliteal pterygium syndrome (PPS) [MIM:119500]. PPS is an autosomal dominant developmental disorder characterized by cleft lip and/or cleft palate, and skin and genital anomalies. Penetrance is incomplete and expressivity is variable. It shows orofacial phenotypic similarities with van der Woude syndrome. Van der Woude and popliteal pterygium syndrome are allelic disorders. Ref.6 Genetic variation in IRF6 is associated with non-syndromic orofacial cleft type 6 (OFC6) [MIM:608864]; also called non-syndromic cleft lip with or without cleft palate 6. Non-syndromic orofacial cleft is a common birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. Ref.11
Sequence similarities	Belongs to the IRF family. Contains 1 tryptophan pentad repeat DNA-binding domain.

Ontologies

Keywords
Biological process	Differentiation Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	DNA-binding
PTM	Ubl conjugation
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	cell cycle arrest Ref.5 Inferred from direct assay. Source: UniProtKB mammary gland epithelial cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell proliferation Ref.5 Inferred from direct assay. Source: UniProtKB positive regulation of transcription Inferred from sequence or structural similarity. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: InterPro transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Ref.4 Ref.5 Inferred from direct assay. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	protein binding Ref.4 Inferred from physical interaction. Source: UniProtKB transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 467	467	Interferon regulatory factor 6		PRO_0000154560
Regions
	DNA binding	9 – 111	103	Tryptophan pentad repeat
Natural variations
	Natural variant	2	1	A → V in VWS. Ref.6 Ref.7		VAR_014961
	Natural variant	6	1	R → C in VWS. Ref.7		VAR_030046
	Natural variant	16	1	A → V in VWS. Ref.8		VAR_030047
	Natural variant	18	1	V → A in VWS; abrogates DNA binding. Ref.6 Ref.14		VAR_014962
	Natural variant	18	1	V → M in VWS; abrogates DNA binding. Ref.6 Ref.14		VAR_014963
	Natural variant	22	1	L → P in VWS and PPS; abrogates DNA binding. Ref.8 Ref.14		VAR_030048
	Natural variant	39	1	P → A in VWS. Ref.6		VAR_014964
	Natural variant	45	1	R → Q in VWS. Ref.9		VAR_030049
	Natural variant	60	1	W → G in PPS; abrogates DNA binding. Ref.6 Ref.14		VAR_014965
	Natural variant	61	1	A → G in VWS. Ref.6		VAR_014966
	Natural variant	64	1	T → I in VWS. Ref.8		VAR_030050
	Natural variant	66	1	K → T in PPS. Ref.6		VAR_014967
	Natural variant	70	1	G → R in VWS; does not affect DNA binding. Ref.6 Ref.14		VAR_014968
	Natural variant	76	1	P → S in VWS; abrogates DNA binding. Ref.6 Ref.14		VAR_014969
	Natural variant	82	1	Q → K in PPS. Ref.6		VAR_014970
	Natural variant	84	1	R → C in PPS; abrogates DNA binding. Ref.6 Ref.14		VAR_014971
	Natural variant	84	1	R → G in VWS; abrogates DNA binding. Ref.10 Ref.14		VAR_030051
	Natural variant	84	1	R → H in PPS; abrogates DNA binding. Ref.6 Ref.14		VAR_014972
	Natural variant	88	1	N → H in VWS. Ref.6		VAR_014973
	Natural variant	89	1	K → E in PPS; abrogates DNA binding. Ref.6 Ref.14		VAR_014974
	Natural variant	90	1	S → G in VWS. Ref.6		VAR_014975
	Natural variant	98	1	D → H in VWS; abrogates DNA binding. Ref.6 Ref.14		VAR_014976
	Natural variant	100	1	T → A in VWS. Ref.8		VAR_030052
	Natural variant	250	1	R → Q in VWS. Ref.6		VAR_014977
	Natural variant	251	1	L → P in VWS. Ref.8		VAR_030053
	Natural variant	273	1	Q → R in VWS. Ref.6		VAR_014978
	Natural variant	274	1	V → I Common polymorphism; 3% in European-descended and 22% in Asian populations; responsible for 12% of the genetic contribution to cleft lip or palate; tripled the risk of recurrence in families that already had 1 affected child. dbSNP rs2235371. Ref.6 Ref.11		VAR_014979
	Natural variant	290 – 296	7	FTSKLLD → L in VWS.		VAR_014980
	Natural variant	294	1	L → P in VWS. Ref.6		VAR_014981
	Natural variant	297	1	V → I in VWS. Ref.6		VAR_014982
	Natural variant	320	1	K → E in VWS. Ref.6		VAR_014983
	Natural variant	321	1	V → M in VWS. Ref.6		VAR_014984
	Natural variant	325	1	G → E in VWS. Ref.6		VAR_014985
	Natural variant	339	1	R → I in VWS. Ref.13		VAR_059080
	Natural variant	345	1	L → P in VWS. Ref.6		VAR_014986
	Natural variant	347	1	C → F in VWS. Ref.6		VAR_014987
	Natural variant	349	1	E → V in VWS. Ref.12		VAR_030054
	Natural variant	369	1	F → S in VWS. Ref.6		VAR_014988
	Natural variant	374	1	C → W in VWS. Ref.6		VAR_014989
	Natural variant	388	1	K → E in VWS. Ref.6		VAR_014990
	Natural variant	396	1	P → S in VWS. Ref.9		VAR_030055
	Natural variant	400	1	R → W in VWS. Ref.7		VAR_030056
	Natural variant	430	1	D → N in PPS. Ref.6		VAR_014991

Sequences

	Sequence		Length	Mass (Da)
	O14896-1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 7E28F5E0F5BA4053	FASTA	467	53,130
	10 20 30 40 50 60 MALHPRRVRL KPWLVAQVDS GLYPGLIWLH RDSKRFQIPW KHATRHSPQQ EEENTIFKAW 70 80 90 100 110 120 AVETGKYQEG VDDPDPAKWK AQLRCALNKS REFNLMYDGT KEVPMNPVKI YQVCDIPQPQ 130 140 150 160 170 180 GSIINPGSTG SAPWDEKDND VDEEDEEDEL DQSQHHVPIQ DTFPFLNING SPMAPASVGN 190 200 210 220 230 240 CSVGNCSPEA VWPKTEPLEM EVPQAPIQPF YSSPELWISS LPMTDLDIKF QYRGKEYGQT 250 260 270 280 290 300 MTVSNPQGCR LFYGDLGPMP DQEELFGPVS LEQVKFPGPE HITNEKQKLF TSKLLDVMDR 310 320 330 340 350 360 GLILEVSGHA IYAIRLCQCK VYWSGPCAPS LVAPNLIERQ KKVKLFCLET FLSDLIAHQK 370 380 390 400 410 420 GQIEKQPPFE IYLCFGEEWP DGKPLERKLI LVQVIPVVAR MIYEMFSGDF TRSFDSGSVR 430 440 450 460 LQISTPDIKD NIVAQLKQLY RILQTQESWQ PMQPTPSMQL PPALPPQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Grossman A., Mittrucker H.W., Antonio L., Ozato K., Mak T.W. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"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]. Tissue: Placenta.
[4]	"Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: identification of a novel serpin partnership." Bailey C.M., Khalkhali-Ellis Z., Kondo S., Margaryan N.V., Seftor R.E.B., Wheaton W.W., Amir S., Pins M.R., Schutte B.C., Hendrix M.J.C. J. Biol. Chem. 280:34210-34217(2005) [PubMed: 16049006] [Abstract] Cited for: INTERACTION WITH SERPINB5, PHOSPHORYLATION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[5]	"Interferon regulatory factor 6 promotes cell cycle arrest and is regulated by the proteasome in a cell cycle-dependent manner." Bailey C.M., Abbott D.E., Margaryan N.V., Khalkhali-Ellis Z., Hendrix M.J.C. Mol. Cell. Biol. 28:2235-2243(2008) [PubMed: 18212048] [Abstract] Cited for: SUBCELLULAR LOCATION, UBIQUITINATION, PHOSPHORYLATION.
[6]	"Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes." Kondo S., Schutte B.C., Richardson R.J., Bjork B.C., Knight A.S., Watanabe Y., Howard E., de Lima R.L.L., Daack-Hirsch S., Sander A., McDonald-McGinn D.M., Zackai E.H., Lammer E.J., Aylsworth A.S., Ardinger H.H., Lidral A.C., Pober B.R., Moreno L. , Arcos-Burgos M., Valencia C., Houdayer C., Bahuau M., Moretti-Ferreira D., Richieri-Costa A., Dixon M.J., Murray J.C. Nat. Genet. 32:285-289(2002) [PubMed: 12219090] [Abstract] Cited for: VARIANTS VWS VAL-2; ALA-18; MET-18; ALA-39; GLY-61; ARG-70; SER-76; HIS-88; GLY-90; HIS-98; GLN-250; ARG-273; 290-PHE--ASP-296 DELINS LEU; PRO-294; ILE-297; GLU-320; MET-321; GLU-325; PRO-345; PHE-347; SER-369; TRP-374 AND GLU-388, VARIANTS PPS GLY-60; THR-66; LYS-82; CYS-84; HIS-84; GLU-89 AND ASN-430, VARIANT ILE-274.
[7]	"Novel mutations in the IRF6 gene for Van der Woude syndrome." Wang X., Liu J., Zhang H., Xiao M., Li J., Yang C., Lin X., Wu Z., Hu L., Kong X. Hum. Genet. 113:382-386(2003) [PubMed: 12920575] [Abstract] Cited for: VARIANTS VWS VAL-2; CYS-6 AND TRP-400.
[8]	"Gene symbol IRF6. Disease: Van der Woude syndrome and popliteal pterygium." Ghassibe M., Revencu N., Bayet B., Gillerot Y., Vanwijck R., Verellen-Dumoulin C., Vikkula M. Hum. Genet. 113:558-558(2003) [PubMed: 14640121] [Abstract] Cited for: VARIANTS VWS VAL-16; ILE-64; ALA-100 AND PRO-251, VARIANT VWS/PPS PRO-22.
[9]	"Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion." Kayano S., Kure S., Suzuki Y., Kanno K., Aoki Y., Kondo S., Schutte B.C., Murray J.C., Yamada A., Matsubara Y. J. Hum. Genet. 48:622-628(2003) [PubMed: 14618417] [Abstract] Cited for: VARIANTS VWS GLN-45 AND SER-396.
[10]	"Gene symbol: IRF6. Disease: Van der Woude syndrome." Item C.B., Turhani D., Thurnher D., Sinko K., Yerit K., Galev K., Wittwer G., Lanre Adeyemo W., Klemens F., Ewers R., Watzinger F. Hum. Genet. 115:175-175(2004) [PubMed: 15300989] [Abstract] Cited for: VARIANT VWS GLY-84.
[11]	"Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate." Zucchero T.M., Cooper M.E., Maher B.S., Daack-Hirsch S., Nepomuceno B., Ribeiro L., Caprau D., Christensen K., Suzuki Y., Machida J., Natsume N., Yoshiura K., Vieira A.R., Orioli I.M., Castilla E.E., Moreno L., Arcos-Burgos M., Lidral A.C. , Field L.L., Liu Y.-E., Ray A., Goldstein T.H., Schultz R.E., Shi M., Johnson M.K., Kondo S., Schutte B.C., Marazita M.L., Murray J.C. N. Engl. J. Med. 351:769-780(2004) [PubMed: 15317890] [Abstract] Cited for: ASSOCIATION OF VARIANT ILE-274 WITH OFC6.
[12]	"A novel missense mutation in Van der Woude syndrome: usefulness of fingernail DNA for genetic analysis." Matsuzawa N., Shimozato K., Natsume N., Niikawa N., Yoshiura K. J. Dent. Res. 85:1143-1146(2006) [PubMed: 17122170] [Abstract] Cited for: VARIANT VWS VAL-349.
[13]	"A novel mutation in IRF6 resulting in VWS-PPS spectrum disorder with renal aplasia." de Medeiros F., Hansen L., Mawlad E., Eiberg H., Asklund C., Tommerup N., Jakobsen L.P. Am. J. Med. Genet. A 146:1605-1608(2008) [PubMed: 18478600] [Abstract] Cited for: VARIANT VWS ILE-339.
[14]	"Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6." Little H.J., Rorick N.K., Su L.-I., Baldock C., Malhotra S., Jowitt T., Gakhar L., Subramanian R., Schutte B.C., Dixon M.J., Shore P. Hum. Mol. Genet. 18:535-545(2009) [PubMed: 19036739] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS VWS/PPS ALA-18; MET-18; PRO-22; GLY-60; ARG-70; SER-76; CYS-84; GLY-84; HIS-84; GLU-89 AND HIS-98.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF027292 mRNA. Translation: AAB84111.1. AL022398 Genomic DNA. Translation: CAA18545.1. BC014852 mRNA. Translation: AAH14852.1.
IPI	IPI00024290.
RefSeq	NP_006138.1.
UniGene	Hs.591415
3D structure databases
HSSP	HSSP built from PDB template 2IRF based on UniProtKB P23906.
ModBase	Search...
Protein-protein interaction databases
STRING	O14896.
Proteomic databases
PeptideAtlas	O14896.
PRIDE	O14896.
Genome annotation databases
Ensembl	ENST00000367021; ENSP00000355988; ENSG00000117595; Homo sapiens. [Genome view] ENST00000456314; ENSP00000403855; ENSG00000117595; Homo sapiens. [Genome view]
GeneID	3664.
KEGG	hsa:3664.
UCSC	uc001hhq.1. human.
Organism-specific databases
CTD	3664.
GeneCards	GC01M208025.
H-InvDB	HIX0001556.
HGNC	HGNC:6121. IRF6.
MIM	119300. phenotype. 119500. phenotype. 607199. gene. 608864. phenotype.
Orphanet	1991. Cleft lip with or without cleft palate. 1300. Pterygium popliteal syndrome, autosomal dominant. 888. Van Der Woude syndrome.
PharmGKB	PA29920.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O14896.
HOVERGEN	O14896.
OMA	DNDVDED.
Gene expression databases
ArrayExpress	O14896.
Bgee	O14896.
CleanEx	HS_IRF6.
Genevestigator	O14896.
GermOnline	ENSG00000117595. Homo sapiens.
Family and domain databases
InterPro	IPR019817. Interferon_regulatory_fac_CS. IPR001346. Interferon_regulatory_factor. IPR019471. Interferon_regulatory_factor-3. IPR017855. SMAD_dom-like. IPR011991. Wing_hlx_DNA_bd. [Graphical view]
Gene3D	G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit. G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit.
Pfam	PF00605. IRF. 1 hit. PF10401. IRF-3. 1 hit. [Graphical view]
PRINTS	PR00267. INTFRNREGFCT.
ProDom	PD002355. IRF. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00348. IRF. 1 hit. [Graphical view]
PROSITE	PS00601. IRF. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	14343.
SOURCE	Search...

Entry information

Entry name

IRF6_HUMAN

Accession

Primary (citable) accession number: O14896

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	January 1, 1998
Last modified:	November 3, 2009
This is version 88 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.