RBCC Red Blood Cell Collection

TFAP2A (AP2TF, TFAP2) [Confidence: low (only semi-automatic identification from reviews)]
Transcription factor AP-2-alpha; AP2-alpha (AP-2 transcription factor; Activating enhancer-binding protein 2-alpha; Activator protein 2; AP-2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P05549
ID AP2A_HUMAN Reviewed; 437 AA.
AC P05549; Q13777; Q5TAV5; Q8N1C6;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Transcription factor AP-2-alpha;
DE Short=AP2-alpha;
DE AltName: Full=AP-2 transcription factor;
DE AltName: Full=Activating enhancer-binding protein 2-alpha;
DE AltName: Full=Activator protein 2;
DE Short=AP-2;
GN Name=TFAP2A; Synonyms=AP2TF, TFAP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3063603;
RA Williams T., Admon A., Luescher B., Tjian R.;
RT "Cloning and expression of AP-2, a cell-type-specific transcription
RT factor that activates inducible enhancer elements.";
RL Genes Dev. 2:1557-1569(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Teratocarcinoma;
RX PubMed=8321221;
RA Buettner R., Kannan P., Imhof A., Bauer R., Yim S.O., Glockshuber R.,
RA Van Dyke M.W., Tainsky M.A.;
RT "An alternatively spliced mRNA from the AP-2 gene encodes a negative
RT regulator of transcriptional activation by AP-2.";
RL Mol. Cell. Biol. 13:4174-4185(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8190633; DOI=10.1093/nar/22.8.1413;
RA Bauer R., Imhof A., Pscherer A., Kopp H., Moser M., Seegers S.,
RA Kerscher M., Tainsky M.A., Hofstaedter F., Buettner R.;
RT "The genomic structure of the human AP-2 transcription factor.";
RL Nucleic Acids Res. 22:1413-1420(1994).
RN [4]
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.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA 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.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Prostate;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP SUBUNIT.
RX PubMed=1998122; DOI=10.1126/science.1998122;
RA Williams T., Tjian R.;
RT "Characterization of a dimerization motif in AP-2 and its function in
RT heterologous DNA-binding proteins.";
RL Science 251:1067-1071(1991).
RN [8]
RP DNA-BINDING.
RX PubMed=2010091;
RA Williams T., Tjian R.;
RT "Analysis of the DNA-binding and activation properties of the human
RT transcription factor AP-2.";
RL Genes Dev. 5:670-682(1991).
RN [9]
RP MUTAGENESIS OF SER-239, AND PHOSPHORYLATION.
RX PubMed=10037142; DOI=10.1016/S0014-5793(99)00021-6;
RA Garcia M.A., Campillos M., Marina A., Valdivieso F., Vazquez J.;
RT "Transcription factor AP-2 activity is modulated by protein kinase A-
RT mediated phosphorylation.";
RL FEBS Lett. 444:27-31(1999).
RN [10]
RP FUNCTION, AND INTERACTION WITH CITED2.
RX PubMed=11694877; DOI=10.1038/ng768;
RA Bamforth S.D., Braganca J., Eloranta J.J., Murdoch J.N., Marques F.I.,
RA Kranc K.R., Farza H., Henderson D.J., Hurst H.C., Bhattacharya S.;
RT "Cardiac malformations, adrenal agenesis, neural crest defects and
RT exencephaly in mice lacking Cited2, a new Tfap2 co-activator.";
RL Nat. Genet. 29:469-474(2001).
RN [11]
RP INTERACTION WITH CITED4.
RX PubMed=11744733; DOI=10.1074/jbc.M110850200;
RA Braganca J., Swingler T., Marques F.I.R., Jones T., Eloranta J.J.,
RA Hurst H.C., Shioda T., Bhattacharya S.;
RT "Human CREB-binding protein/p300-interacting transactivator with ED-
RT rich tail (CITED) 4, a new member of the CITED family, functions as a
RT co-activator for transcription factor AP-2.";
RL J. Biol. Chem. 277:8559-8565(2002).
RN [12]
RP INTERACTION WITH UBE2I, AND SUMOYLATION AT LYS-10.
RX PubMed=12072434; DOI=10.1074/jbc.M202780200;
RA Eloranta J.J., Hurst H.C.;
RT "Transcription factor AP-2 interacts with the SUMO-conjugating enzyme
RT UBC9 and is sumolated in vivo.";
RL J. Biol. Chem. 277:30798-30804(2002).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, DNA-BINDING, AND INTERACTION WITH
RP CITED2 AND EP300.
RX PubMed=12586840; DOI=10.1074/jbc.M208144200;
RA Braganca J., Eloranta J.J., Bamforth S.D., Ibbitt J.C., Hurst H.C.,
RA Bhattacharya S.;
RT "Physical and functional interactions among AP-2 transcription
RT factors, p300/CREB-binding protein, and CITED2.";
RL J. Biol. Chem. 278:16021-16029(2003).
RN [14]
RP INTERACTION WITH RALBP1.
RX PubMed=12775724; DOI=10.1074/jbc.M302191200;
RA Rosse C., L'Hoste S., Offner N., Picard A., Camonis J.;
RT "RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to
RT phosphorylate epsin during the switch off of endocytosis in mitosis.";
RL J. Biol. Chem. 278:30597-30604(2003).
RN [15]
RP INTERACTION WITH WWOX, AND DOMAIN.
RX PubMed=15548692; DOI=10.1158/0008-5472.CAN-04-2055;
RA Aqeilan R.I., Palamarchuk A., Weigel R.J., Herrero J.J., Pekarsky Y.,
RA Croce C.M.;
RT "Physical and functional interactions between the Wwox tumor
RT suppressor protein and the AP-2gamma transcription factor.";
RL Cancer Res. 64:8256-8261(2004).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP INTERACTION WITH KCTD1.
RX PubMed=19115315; DOI=10.1002/jcb.22002;
RA Ding X., Luo C., Zhou J., Zhong Y., Hu X., Zhou F., Ren K., Gan L.,
RA He A., Zhu J., Gao X., Zhang J.;
RT "The interaction of KCTD1 with transcription factor AP-2alpha inhibits
RT its transactivation.";
RL J. Cell. Biochem. 106:285-295(2009).
RN [18]
RP INTERACTION WITH KCTD15.
RX PubMed=23382213; DOI=10.1073/pnas.1300203110;
RA Zarelli V.E., Dawid I.B.;
RT "Inhibition of neural crest formation by Kctd15 involves regulation of
RT transcription factor AP-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:2870-2875(2013).
RN [19]
RP VARIANTS BOFS PRO-249; GLY-254; GLY-255 AND GLU-262.
RX PubMed=18423521; DOI=10.1016/j.ajhg.2008.03.005;
RA Milunsky J.M., Maher T.A., Zhao G., Roberts A.E., Stalker H.J.,
RA Zori R.T., Burch M.N., Clemens M., Mulliken J.B., Smith R., Lin A.E.;
RT "TFAP2A mutations result in branchio-oculo-facial syndrome.";
RL Am. J. Hum. Genet. 82:1171-1177(2008).
CC -!- FUNCTION: Sequence-specific DNA-binding protein that interacts
CC with inducible viral and cellular enhancer elements to regulate
CC transcription of selected genes. AP-2 factors bind to the
CC consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in
CC a large spectrum of important biological functions including
CC proper eye, face, body wall, limb and neural tube development.
CC They also suppress a number of genes including MCAM/MUC18, C/EBP
CC alpha and MYC. AP-2-alpha is the only AP-2 protein required for
CC early morphogenesis of the lens vesicle. Together with the CITED2
CC coactivator, stimulates the PITX2 P1 promoter transcription
CC activation. Associates with chromatin to the PITX2 P1 promoter
CC region.
CC -!- SUBUNIT: Binds DNA as a dimer. Can form homodimers or heterodimers
CC with other AP-2 family members. Interacts with WWOX. Interacts
CC with CITED4. Interacts with UBE2I. Interacts with RALBP1 in a
CC complex also containing EPN1 and NUMB during interphase and
CC mitosis. Interacts with KCTD1; this interaction represses
CC transcription activation. Interacts (via C-terminus) with CITED2
CC (via C-terminus); the interaction stimulates TFAP2A-
CC transcriptional activation. Interacts (via N-terminus) with EP300
CC (via N-terminus); the interaction requires CITED2. Interacts with
CC KCTD15; this interaction inhibits TFAP2A transcriptional
CC activation.
CC -!- INTERACTION:
CC Q09472:EP300; NbExp=7; IntAct=EBI-347351, EBI-447295;
CC P06748:NPM1; NbExp=6; IntAct=EBI-347351, EBI-78579;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Comment=Experimental confirmation may be lacking for some
CC isoforms;
CC Name=1; Synonyms=AP-2A;
CC IsoId=P05549-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05549-5; Sequence=VSP_043268;
CC Note=No experimental confirmation available;
CC Name=4; Synonyms=AP-2B;
CC IsoId=P05549-2; Sequence=VSP_006401;
CC Note=May be an aberrantly processed form with no significant
CC distribution in vivo;
CC Name=5;
CC IsoId=P05549-6; Sequence=VSP_047050;
CC Note=Gene prediction based on EST data;
CC -!- DOMAIN: The WW-binding motif mediates interaction with WWOX (By
CC similarity).
CC -!- PTM: Sumoylated on Lys-10; which inhibits transcriptional activity
CC (Probable).
CC -!- DISEASE: Branchiooculofacial syndrome (BOFS) [MIM:113620]: A
CC syndrome characterized by growth retardation, bilateral branchial
CC sinus defects with hemangiomatous, scarred skin, cleft lip with or
CC without cleft palate, pseudocleft of the upper lip, nasolacrimal
CC duct obstruction, low set ears with posterior rotation, a
CC malformed, asymmetrical nose with a broad bridge and flattened
CC tip, conductive or sensorineural deafness, ocular and renal
CC anomalies. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AP-2 family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Activatin protein 2 entry;
CC URL="http://en.wikipedia.org/wiki/Activating_protein_2";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TFAP2AID42526ch6p24.html";
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DR EMBL; M36711; AAA35539.1; -; mRNA.
DR EMBL; M61156; AAA02487.1; -; mRNA.
DR EMBL; X52611; CAA36842.1; -; mRNA.
DR EMBL; X77343; CAB59735.1; -; Genomic_DNA.
DR EMBL; AL138885; CAI20064.1; -; Genomic_DNA.
DR EMBL; CH471087; EAW55249.1; -; Genomic_DNA.
DR EMBL; BC017754; AAH17754.1; -; mRNA.
DR PIR; A31752; A31752.
DR RefSeq; NP_001027451.1; NM_001032280.2.
DR RefSeq; NP_001035890.1; NM_001042425.1.
DR RefSeq; NP_003211.1; NM_003220.2.
DR UniGene; Hs.519880; -.
DR ProteinModelPortal; P05549; -.
DR IntAct; P05549; 6.
DR MINT; MINT-1524309; -.
DR STRING; 9606.ENSP00000368924; -.
DR PhosphoSite; P05549; -.
DR DMDM; 135302; -.
DR PaxDb; P05549; -.
DR PRIDE; P05549; -.
DR DNASU; 7020; -.
DR Ensembl; ENST00000319516; ENSP00000316516; ENSG00000137203.
DR Ensembl; ENST00000379604; ENSP00000368924; ENSG00000137203.
DR Ensembl; ENST00000379608; ENSP00000368928; ENSG00000137203.
DR Ensembl; ENST00000482890; ENSP00000418541; ENSG00000137203.
DR GeneID; 7020; -.
DR KEGG; hsa:7020; -.
DR UCSC; uc003myr.3; human.
DR CTD; 7020; -.
DR GeneCards; GC06M010393; -.
DR HGNC; HGNC:11742; TFAP2A.
DR HPA; CAB000326; -.
DR HPA; HPA028850; -.
DR MIM; 107580; gene.
DR MIM; 113620; phenotype.
DR neXtProt; NX_P05549; -.
DR Orphanet; 1297; Branchio-oculo-facial syndrome.
DR PharmGKB; PA36459; -.
DR eggNOG; NOG300693; -.
DR HOGENOM; HOG000231737; -.
DR HOVERGEN; HBG002455; -.
DR InParanoid; P05549; -.
DR KO; K09176; -.
DR PhylomeDB; P05549; -.
DR ChiTaRS; TFAP2A; human.
DR GeneWiki; TFAP2A; -.
DR GenomeRNAi; 7020; -.
DR NextBio; 27423; -.
DR PMAP-CutDB; P05549; -.
DR PRO; PR:P05549; -.
DR ArrayExpress; P05549; -.
DR Bgee; P05549; -.
DR CleanEx; HS_TFAP2A; -.
DR Genevestigator; P05549; -.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; TAS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0001078; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription; IDA:UniProtKB.
DR GO; GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; IDA:UniProtKB.
DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0000980; F:RNA polymerase II distal enhancer sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0001105; F:RNA polymerase II transcription coactivator activity; IEA:Ensembl.
DR GO; GO:0001106; F:RNA polymerase II transcription corepressor activity; IEA:Ensembl.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0021506; P:anterior neuropore closure; IEA:Ensembl.
DR GO; GO:0071711; P:basement membrane organization; IEA:Ensembl.
DR GO; GO:0060349; P:bone morphogenesis; ISS:UniProtKB.
DR GO; GO:0071281; P:cellular response to iron ion; IDA:UniProtKB.
DR GO; GO:0061303; P:cornea development in camera-type eye; IEA:Ensembl.
DR GO; GO:0010172; P:embryonic body morphogenesis; IEA:Ensembl.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; ISS:UniProtKB.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; ISS:UniProtKB.
DR GO; GO:0009880; P:embryonic pattern specification; IEA:Ensembl.
DR GO; GO:0048730; P:epidermis morphogenesis; IEA:Ensembl.
DR GO; GO:0061029; P:eyelid development in camera-type eye; ISS:UniProtKB.
DR GO; GO:0060325; P:face morphogenesis; IEA:Ensembl.
DR GO; GO:0021884; P:forebrain neuron development; IEA:Ensembl.
DR GO; GO:0042472; P:inner ear morphogenesis; IMP:UniProtKB.
DR GO; GO:0003334; P:keratinocyte development; IEA:Ensembl.
DR GO; GO:0001822; P:kidney development; IMP:UniProtKB.
DR GO; GO:0060235; P:lens induction in camera-type eye; IEA:Ensembl.
DR GO; GO:0072210; P:metanephric nephron development; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl.
DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IDA:UniProtKB.
DR GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; IDA:UniProtKB.
DR GO; GO:0014032; P:neural crest cell development; IEA:Ensembl.
DR GO; GO:0021623; P:oculomotor nerve formation; ISS:UniProtKB.
DR GO; GO:0003409; P:optic cup structural organization; ISS:UniProtKB.
DR GO; GO:0003404; P:optic vesicle morphogenesis; ISS:UniProtKB.
DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR GO; GO:0060021; P:palate development; IMP:UniProtKB.
DR GO; GO:0030501; P:positive regulation of bone mineralization; IDA:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0070172; P:positive regulation of tooth mineralization; IDA:UniProtKB.
DR GO; GO:0045595; P:regulation of cell differentiation; IDA:UniProtKB.
DR GO; GO:0045664; P:regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0010842; P:retina layer formation; IEP:UniProtKB.
DR GO; GO:0007605; P:sensory perception of sound; IMP:UniProtKB.
DR GO; GO:0048485; P:sympathetic nervous system development; IEA:Ensembl.
DR GO; GO:0021559; P:trigeminal nerve development; ISS:UniProtKB.
DR InterPro; IPR004979; TF_AP2.
DR InterPro; IPR008121; TF_AP2_alpha_N.
DR InterPro; IPR013854; TF_AP2_C.
DR PANTHER; PTHR10812; PTHR10812; 1.
DR Pfam; PF03299; TF_AP-2; 1.
DR PRINTS; PR01749; AP2ATNSCPFCT.
DR PRINTS; PR01748; AP2TNSCPFCT.
PE 1: Evidence at protein level;
KW Activator; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; DNA-binding;
KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1 437 Transcription factor AP-2-alpha.
FT /FTId=PRO_0000184796.
FT REGION 280 410 H-S-H (helix-span-helix), dimerization.
FT MOTIF 57 62 WW-binding.
FT COMPBIAS 29 117 Gln/Pro-rich (transactivation domain).
FT MOD_RES 239 239 Phosphoserine; by PKA.
FT CROSSLNK 10 10 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO)
FT (Probable).
FT VAR_SEQ 1 15 MLWKLTDNIKYEDCE -> MLVHSFSAM (in isoform
FT 2).
FT /FTId=VSP_043268.
FT VAR_SEQ 1 15 MLWKLTDNIKYEDCE -> MSILAKMGDWQ (in
FT isoform 5).
FT /FTId=VSP_047050.
FT VAR_SEQ 296 437 EAVHLARDFGYVCETEFPAKAVAEFLNRQHSDPNEQVTRKN
FT MLLATKQICKEFTDLLAQDRSPLGNSRPNPILEPGIQSCLT
FT HFNLISHGFGSPAVCAAVTALQNYLTEALKAMDKMYLSNNP
FT NSHTDNNAKSSDKEEKHRK -> KRIHLLTRRNFLLGKWII
FT FSGQMFGRILCQLGSFIFAENIARCEWNYFMAKRNICMYSY
FT TSILLPSFPLP (in isoform 4).
FT /FTId=VSP_006401.
FT VARIANT 249 249 L -> P (in BOFS).
FT /FTId=VAR_045838.
FT VARIANT 254 254 R -> G (in BOFS).
FT /FTId=VAR_045839.
FT VARIANT 255 255 R -> G (in BOFS).
FT /FTId=VAR_045840.
FT VARIANT 262 262 G -> E (in BOFS).
FT /FTId=VAR_045841.
FT MUTAGEN 239 239 S->A: No phosphorylation.
SQ SEQUENCE 437 AA; 48062 MW; FB8FA33C3AEED71F CRC64;
MLWKLTDNIK YEDCEDRHDG TSNGTARLPQ LGTVGQSPYT SAPPLSHTPN ADFQPPYFPP
PYQPIYPQSQ DPYSHVNDPY SLNPLHAQPQ PQHPGWPGQR QSQESGLLHT HRGLPHQLSG
LDPRRDYRRH EDLLHGPHAL SSGLGDLSIH SLPHAIEEVP HVEDPGINIP DQTVIKKGPV
SLSKSNSNAV SAIPINKDNL FGGVVNPNEV FCSVPGRLSL LSSTSKYKVT VAEVQRRLSP
PECLNASLLG GVLRRAKSKN GGRSLREKLD KIGLNLPAGR RKAANVTLLT SLVEGEAVHL
ARDFGYVCET EFPAKAVAEF LNRQHSDPNE QVTRKNMLLA TKQICKEFTD LLAQDRSPLG
NSRPNPILEP GIQSCLTHFN LISHGFGSPA VCAAVTALQN YLTEALKAMD KMYLSNNPNS
HTDNNAKSSD KEEKHRK
//

MIM 107580
*RECORD*
*FIELD* NO
107580
*FIELD* TI
*107580 TRANSCRIPTION FACTOR AP2-ALPHA; TFAP2A
;;AP2;;
ACTIVATING ENHANCER-BINDING PROTEIN 2-ALPHA;;
read moreAP2 TRANSCRIPTION FACTOR; AP2TF;;
TFAP2
*FIELD* TX

DESCRIPTION

AP2-alpha is a 52-kD retinoic acid-inducible and developmentally
regulated activator of transcription that binds to a consensus
DNA-binding sequence CCCCAGGC in the SV40 and metallothionein (156350)
promoters (Mitchell et al., 1987; Williams et al., 1988).

CLONING

Williams et al. (1988) isolated and characterized human TFAP2A, which
they designated AP2, encoding a 436-amino acid protein.

Buettner et al. (1993) described an alternatively spliced form of AP2
that does not bind the AP2 consensus site and strongly inhibits binding
of endogenous AP2, thus acting as a dominant-negative inhibitor. Gestri
et al. (2009) noted that alternative splicing of exon 5a results in a
TFAP2A isoform of 365 amino acids with an alternative C-terminal
sequence.

Gestri et al. (2009) analyzed TFAP2A expression in mouse and human
embryos and human fetal stage F2. Expression in the mouse was seen in
the nasal process, palate, and within the CNS. During human embryonic
development, TFAP2A was first seen in the anterior epithelium of the
lens at cleavage stage (CS) 15. At CS18, TFAP2A was expressed more
strongly in the anterior epithelium of the lens and also in the ganglion
layer of the neural retina, and at CS22, in the equatorial region of the
lens epithelium, secondary lens fibers, and throughout the ganglion cell
layer of the neural retina. TFAP2A expression was still visible but
weaker in the retina of F2 human eyes.

GENE STRUCTURE

Bauer et al. (1994) described the genomic organization of the TFAP2A
gene, including the promoter. The mature AP2 mRNA is spliced from 7
exons distributed over 18 kb of genomic DNA. They demonstrated that the
promoter of the AP2TF gene is subject to positive autoregulation by its
own gene product. A consensus AP2 binding site was located at position
-622 with respect to the ATG initiation codon.

Gestri et al. (2009) noted that TFAP2A has 3 alternative transcription
start sites designated exons 1a, 1b, and 1c as well as an alternative
exon 5a.

MAPPING

By analysis of somatic cell hybrids and in situ hybridization to
chromosomes, Gaynor et al. (1991) mapped the TFAP2A gene to chromosome
6p24-p22.3. Williamson et al. (1996) identified 2 other members of this
gene family, AP2-beta (TFAP2B; 601601) and AP2-gamma (TFAP2C; 601602).
Using FISH, Warren et al. (1996) mapped the homologous mouse gene,
Tcfap2a, to chromosome 13A5-B1. Williamson et al. (1996) obtained human
and mouse genomic clones for AP2-alpha and used FISH to confirm the
location of the gene to human chromosome 6p24 and to mouse 13A5-B1.

GENE FUNCTION

Davies et al. (1999) reported a child with microphthalmia and corneal
clouding and a number of other dysmorphic features, including
hypertelorism, micrognathia, dysplastic ears, thin limbs, and congenital
cardiac defects. This child had an interstitial deletion of 6p25-p24
that included AP2-alpha. Davies et al. (1999) suggested that AP2-alpha
may be involved in anterior eye chamber development.

Zhu et al. (2001) found that SV40 transformation of human lung
fibroblast cell lines was associated with cytosine methylation of the
AP2-alpha promoter at 2 sites, including the KLF12 (607531)-binding
site. They concluded that hypermethylation at the KLF12 site would tend
to relieve KLF12-mediated suppression of AP2 promoter activity.

By deletion analysis of the 5-prime-flanking region of the TFAP2A gene,
Cheng and Handwerger (2003) determined that the proximal 152 bp are
essential for minimal promoter activity and that a 140-bp fragment from
nucleotides -1279 to -1139 acts as an enhancer of basal transcriptional
activity. Ligation of the 140-bp fragment to a minimal TFAP2A promoter
or a heterologous simian virus 40 promoter luciferase reporter plasmid
conferred enhancer activity in trophoblast cells. In deoxyribonuclease I
footprint studies, nuclear extracts from trophoblast cells protected 2
regions of the 140-bp fragment, E2 and E3. Site-directed mutagenesis of
an ETS1 (164720)-binding site in E2 significantly inhibited TFAP2A
enhancer activity. Gel shift and supershift assays indicated that ETS1
binds to the ETS site in E2, and overexpression of ETS1 in transfection
studies induced TFAP2A promoter activity. As the transcription factor
ETS1 is abundant in trophoblast cells, Cheng and Handwerger (2003)
concluded that these investigations strongly suggested that TFAP2A gene
expression in the placenta is enhanced by a cis-acting element at
nucleotides -1279 to -1139 that contains a critical ETS1-binding site.

Zarelli and Dawid (2013) found that human and zebrafish KCTD15 (615240)
inhibited AP2-alpha-dependent expression of a reporter gene. KCTD15 did
not prevent AP2-alpha dimer formation or binding of AP2-alpha to
chromatin. KCTD15 directly bound a proline-rich region in the N-terminal
activation domain of zebrafish AP2-alpha. Mutation of pro59 within this
region inhibited KCTD15 binding, but it had no effect on DNA binding by
AP2-alpha or AP2-alpha transactivation activity. KCTD15 inhibited
AP2-alpha-dependent expression of neural crest markers in Xenopus animal
cap assays. Zarelli and Dawid (2013) concluded that KCTD15 is a negative
regulator of AP2-alpha that regulates neural crest formation during
embryonic development.

Montagnac et al. (2013) reported that clathrin-coated pits control
microtubule acetylation through a direct interaction of alpha-tubulin
acetyltransferase (ATAT1; 615556) with the clathrin adaptor AP2.
Montagnac et al. (2013) observed that about one-third of growing
microtubule ends contact and pause at clathrin-coated pits and that loss
of clathrin-coated pits decreases lys40 acetylation levels. Montagnac et
al. (2013) showed that ATAT1 localizes to clathrin-coated pits through a
direct interaction with AP2 that is required for microtubule
acetylation. In migrating cells, the polarized orientation of acetylated
microtubules correlates with clathrin-coated pit accumulation at the
leading edge, and interaction of ATAT1 with AP2 is required for
directional migration. Montagnac et al. (2013) concluded that
microtubules contacting clathrin-coated pits become acetylated by ATAT1.
In migrating cells, this mechanism ensures the acetylation of
microtubules oriented toward the leading edge, thus promoting
directional cell locomotion and chemotaxis.

MOLECULAR GENETICS

Milunsky et al. (2008) studied a mother and son with branchiooculofacial
syndrome (BOFS; 113620) and detected a 3.2-Mb deletion at chromosome
6p24.3. Sequencing of candidate genes in that region in 4 additional
unrelated BOFS patients revealed 4 different de novo missense mutations
in the highly conserved exons 4 and 5 of the TFAP2A gene (see, e.g.,
107580.0001 and 107580.0002).

Gestri et al. (2009) analyzed the TFAP2A gene in 37 patients with
developmental eye defects plus variable defects associated with BOFS and
identified 2 heterozygous mutations in 2 patients (107580.0003 and
107580.0004, respectively). In addition, multiplex ligation-dependent
probe amplification (MPLA) revealed a heterozygous deletion of the
TFAP2A gene in 2 sibs with BOFS and their mildly affected father,
previously reported by Fielding and Fryer (1992).

In a 4-year-old Turkish girl with sensorineural hearing loss and
features of BOFS, Tekin et al. (2009) identified a heterozygous
deletion/insertion mutation in the TFAP2A gene (107580.0005).

In 2 families and 3 sporadic patients with BOFS, Reiber et al. (2010)
identified 4 heterozygous mutations, all within the highly conserved
exons 4 through 6 of the TFAP2A gene, respectively (see, e.g.,
107580.0001 and 107580.0006-107580.0007). The authors noted that these
exons are almost free of any single-nucleotide polymorphisms and are
evolutionarily highly conserved.

For discussion of a possible role of TFAP2A in cleft lip/palate, see
CLP1 (119530).

ANIMAL MODEL

To study the role of AP2 during embryogenesis, Schorle et al. (1996)
undertook a targeted mutagenesis of the Ap2 gene in the mouse. They
reported that Ap2 -/- mice died perinatally with cranioabdominoschisis
and severe dysmorphogenesis of the face, skull, sensory organs, and
cranial ganglia. Failure of cranial closure between days 9 and 9.5
postcoitum coincided with increased apoptosis in the midbrain, anterior
hindbrain, and proximal mesenchyme of the first branchial arch, but did
not involve loss of expression of 'Twist' (601622) or Pax3 (606597), 2
other regulatory genes known to be required for cranial closure.

Homozygous knockout mice for Ap2-alpha were shown by Zhang et al. (1996)
to have observable neural tube defects at day 9.5 which were followed by
craniofacial and body wall abnormalities later in embryogenesis. This is
consistent with the developmental expression of AP2-alpha in tissues of
ectodermal origin.

Lim et al. (2005) tested the role of the transcription factor AP2-alpha
in regulating Fmr1 (309550) expression. Chromatin immunoprecipitation
showed that AP2-alpha associated with the Fmr1 promoter in vivo. Fmr1
transcript levels were reduced approximately 4-fold in homozygous null
AP2-alpha mutant mice at embryonic day 18.5 when compared with normal
littermates. AP2-alpha exhibited a strong gene dosage effect, with
heterozygous mice showing a approximately 2-fold reduction in Fmr1
levels. Examination of conditional AP2-alpha mutant mice indicated that
the transcription factor played a major role in regulating Fmr1
expression in embryos, but not in adults. Overexpression of a
dominant-negative AP2-alpha in Xenopus embryos led to reduced Fmr1
levels. Exogenous wildtype AP2-alpha rescued Fmr1 expression in embryos
where endogenous AP2-alpha had been suppressed. Lim et al. (2005)
concluded that AP2-alpha associates with the Fmr1 promoter in vivo and
selectively regulates Fmr1 transcription during embryonic development.

After morpholino knockdown of tfap2a function in zebrafish, Gestri et
al. (2009) observed a range of eye anomalies, which were frequently
asymmetric and included microphthalmia, mild coloboma, and severe
coloboma in which ventral retinal tissue, including retinal pigment
epithelium, protruded from the back of the eye towards the midline of
the brain. Pharyngeal cartilages were also affected in tfap2a morphants
with the ceratohyal reduced in size and oriented medially instead of
rostrally. Less severe defects were seen in more posterior arches.

Bassett et al. (2010) showed that patterning and morphogenetic defects
in the Ap2-alpha knockout optic neuroepithelium began at the optic
vesicle stage. During subsequent optic cup formation, ectopic neural
retina and optic stalk-like tissue replaced regions of retinal pigment
epithelium. Ap2-alpha knockout eyes also displayed coloboma in the
ventral retina, and a rare phenotype in which the optic stalk completely
failed to extend, causing the optic cups to be drawn inward to the
midline. There was increased sonic hedgehog (SHH; 600725) signaling in
the Ap2-alpha knockout forebrain neuroepithelium, which likely
contributed to multiple aspects of the ocular phenotype, including
expansion of Pax2 (167409)-positive optic stalk-like tissue into the
optic cup. The authors suggested that loss of AP2-alpha in multiple
tissues in the craniofacial region leads to severe optic cup and optic
stalk abnormalities by disturbing the tissue-tissue interactions
required for ocular development.

*FIELD* AV
.0001
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, ARG255GLY

In an 18-year-old man with branchiooculofacial syndrome (BOFS; 113620),
previously studied by Lin et al. (2000), Milunsky et al. (2008)
identified a de novo 10529A-G transition in exon 4 of the TFAP2A gene,
resulting in an arg255-to-gly (R255G) substitution at a highly conserved
residue in the basic region of the DNA-binding domain, a change that
replaces a charged polar side chain with a nonpolar side chain with a
predicted conformational space change. The mutation was not found in
more than 300 controls.

In a mother and daughter with BOFS, as well as an unrelated sporadic
BOFS patient, Reiber et al. (2010) identified heterozygosity for the
R255G mutation in the TFAP2A gene. Noting that R255G had been found in 3
of 11 unrelated mutation-positive patients, Reiber et al. (2010)
suggested that it might represent a recurrent mutation causing BOFS.

.0002
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, GLY262GLU

In a 17-year-old man with branchiooculofacial syndrome (BOFS; 113620),
previously studied by Lin et al. (2000), Milunsky et al. (2008)
identified a de novo 12448C-T transition in exon 5 of the TFAP2A gene,
resulting in an gly262-to-glu (G262E) substitution at a highly conserved
residue in the basic region of the DNA-binding domain, a change that
replaces a nonpolar side chain with a charged polar side chain. The
mutation was not found in more than 300 controls. Milunsky et al. (2008)
stated that this was the first BOFS patient reported with
medulloblastoma.

.0003
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, 12-BP DEL, NT697

In a 5-year-old boy with branchiooculofacial syndrome (BOFS; 113620),
Gestri et al. (2009) identified a de novo heterozygous 12-bp deletion
(697del12) in the basic domain of the TFAP2A gene, resulting in deletion
of 4 amino acids, from glu233 to arg236. The patient had classic
features of BOFS, including high-arched palate, prominent philtrum,
narrow ear canals, abnormal pinnae, and periorbital and scalp cysts. His
eye findings included a right cystic remnant and mildly microphthalmic
left eye with a reduced corneal diameter, iris coloboma, primary
aphakia, and a large posterior chorioretinal coloboma.

.0004
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, PHE319SER

In a 10-month-old female infant with severe eye defects but a nonclassic
branchiooculofacial syndrome phenotype (BOFS; 113620), Gestri et al.
(2009) identified a heterozygous 956T-C transition in exon 5a the TFAP2A
gene, resulting in a phe319-to-ser (F319S) substitution at a conserved
residue in the alternatively spliced isoform of TFAP2A. The mutation,
which was not found in 189 control samples, was inherited from her
apparently unaffected father and segregated with polydactyly on the
paternal side. The patient had right microphthalmia with sclerocornea,
primary aphakia, and localized tractional retinal detachment, and an
extremely microphthalmic left eye with sclerocornea. Her systemic
features, which were not classic for BOFS, included atrial septal defect
with an enlarged anomalous blood vessel draining into the right atrium,
and facial capillary hemangioma.

.0005
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, 18-BP DEL/6-BP INS, NT828

In a 4-year-old Turkish girl with sensorineural hearing loss and
features of branchiooculofacial syndrome (BOFS; 113620), Tekin et al.
(2009) identified heterozygosity for a de novo 18-bp deletion and 6-bp
insertion (828delCTGCCTGCAGGGAGACGTinsAGGATT) in exon 5 of the TFAP2A
gene, resulting in insertion of arginine and isoleucine residues at
codon 276. Tekin et al. (2009) stated that this mutation differed from
those previously reported in BOFS patients without sensorineural hearing
loss in that it involved both DNA-binding and dimerization domains; they
suggested that the patient's inner ear malformation might be related to
impaired dimerization of TFAP2A.

.0006
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, GLU269LYS

In 5 affected members of a family with branchiooculofacial syndrome
(BOFS; 113620), originally reported by Lin et al. (1995), Reiber et al.
(2010) identified heterozygosity for an 886G-A transition in exon 6 of
the TFAP2A gene, resulting in a glu296-to-lys (E296K) substitution at a
highly conserved residue.

.0007
BRANCHIOOCULOFACIAL SYNDROME
TFAP2A, ARG237GLN

In a boy with mild branchiooculofacial syndrome (BOFS; 113620) who had a
pseudocleft lip consisting only of a philtral ridge, Reiber et al.
(2010) identified heterozygosity for a 710G-A transition in exon 4 of
the TFAP2A gene, resulting in an arg237-to-gln (R237Q) substitution at a
highly conserved residue.

*FIELD* RF
1. Bassett, E. A.; Williams, T.; Zacharias, A. L.; Gage, P. J.; Fuhrmann,
S.; West-Mays, J. A.: AP-2-alpha knockout mice exhibit optic cup
patterning defects and failure of optic stalk morphogenesis. Hum.
Molec. Genet. 19: 1791-1804, 2010.

2. Bauer, R.; Imhof, A.; Pscherer, A.; Kopp, H.; Moser, M.; Seegers,
S.; Kerscher, M.; Tainsky, M. A.; Hofstaedter, F.; Buettner, R.:
The genomic structure of the human AP-2 transcription factor. Nucleic
Acids Res. 22: 1413-1420, 1994.

3. Buettner, R.; Kannan, P.; Imhof, A.; Bauer, R.; Yim, S. O.; Glockshuber,
R.; Van Dyke, M. W.; Tainsky, M. A.: An alternatively spliced mRNA
from the AP-2 gene encodes a negative regulator of transcriptional
activation by AP-2. Molec. Cell. Biol. 13: 4174-4185, 1993.

4. Cheng, Y.-H.; Handwerger, S.: Identification of an enhancer of
the human activating protein-2-alpha gene that contains a critical
Ets1 binding site. J. Clin. Endocr. Metab. 88: 3305-3311, 2003.

5. Davies, A. F.; Mirza, G.; Flinter, F.; Ragoussis, J.: An interstitial
deletion of 6p24-p25 proximal to the FKHL7 locus and including AP-2-alpha
that affects anterior eye chamber development. J. Med. Genet. 36:
708-710, 1999.

6. Fielding, D. W.; Fryer, A. E.: Recurrence of orbital cysts in
the branchio-oculo-facial syndrome. J. Med. Genet. 29: 430-431,
1992.

7. Gaynor, R. B.; Muchardt, C.; Xia, Y.; Klisak, I.; Mohandas, T.;
Sparkes, R. S.; Lusis, A. J.: Localization of the gene for the DNA-binding
protein AP-2 to human chromosome 6p22.3-pter. Genomics 10: 1100-1102,
1991.

8. Gestri, G.; Osborne, R. J.; Wyatt, A. W.; Gerrelli, D.; Gribble,
S.; Stewart, H.; Fryer, A.; Bunyan, D. J.; Prescott, K.; Collin, J.
R. O.; Fitzgerald, T.; Robinson, D.; Carter, N. P.; Wilson, S. W.;
Ragge, N. K.: Reduced TFAP2A function causes variable optic fissure
closure and retinal defects and sensitizes eye development to mutations
in other morphogenetic regulators. Hum. Genet. 126: 791-803, 2009.

9. Lim, J. H.; Booker, A. B.; Luo, T.; Williams, T.; Furuta, Y.; Lagutin,
O.; Oliver, G.; Sargent, T. D.; Fallon, J. R.: AP-2-alpha selectively
regulates fragile X mental retardation-1 gene transcription during
embryonic development. Hum. Molec. Genet. 14: 2027-2034, 2005.

10. Lin, A. E.; Gorlin, R. J.; Lurie, I. W.; Brunner, H. G.; van der
Burgt, I.; Naumchik, I. V.; Rumyantseva, N. V.; Stengel-Rutkowski,
S.; Rosenbaum, K.; Meinecke, P.; Muller, D.: Further delineation
of the branchio-oculo-facial syndrome. Am. J. Med. Genet. 56: 42-59,
1995.

11. Lin, A. E.; Semina, E. V.; Daack-Hirsch, S.; Roeder, E. R.; Curry,
C. J. R.; Rosenbaum, K.; Weaver, D. D.; Murray, J. C.: Exclusion
of the branchio-oto-renal syndrome locus (EYA1) from patients with
branchio-oculo-facial syndrome. Am. J. Med. Genet. 91: 387-390,
2000. Note: Erratum: Am. J. Med. Genet. 93: 169 only, 2000.

12. Milunsky, J. M.; Maher, T. A.; Zhao, G.; Roberts, A. E.; Stalker,
H. J.; Zori, R. T.; Burch, M. N.; Clemens, M.; Mulliken, J. B.; Smith,
R.; Lin, A. E.: TFAP2A mutations result in branchio-oculo-facial
syndrome. Am. J. Hum. Genet. 82: 1171-1177, 2008. Note: Erratum:
Am. J. Hum. Genet. 84: 301 only, 2009.

13. Mitchell, P. J.; Wang, C.; Tjian, R.: Positive and negative regulation
of transcription in vitro: enhancer-binding protein AP-2 is inhibited
by SV40 T antigen. Cell 50: 847-861, 1987.

14. Montagnac, G.; Meas-Yedid, V.; Irondelle, M.; Castro-Castro, A.;
Franco, M.; Shida, T.; Nachury, M. V.; Benmerah, A.; Olivo-Marin,
J.-C.; Chavrier, P.: Alpha-TAT1 catalyses microtubule acetylation
at clathrin-coated pits. Nature 502: 567-570, 2013.

15. Reiber, J.; Sznajer, Y.; Posteguillo, E. G.; Muller, D.; Lyonnet,
S.; Baumann, C.; Just, W.: Additional clinical and molecular analyses
of TFAP2A in patients with the branchio-oculo-facial syndrome. Am.
J. Med. Genet. 152A: 994-999, 2010.

16. Schorle, H.; Meier, P.; Buchert, M.; Jaenisch, R.; Mitchell, P.
J.: Transcription factor AP-2 essential for cranial closure and craniofacial
development. Nature 381: 235-238, 1996.

17. Tekin, M.; Sirmaci, A.; Yuksel-Konuk, B.; Fitoz, S.; Sennaroglu,
L.: A complex TFAP2A allele is associated with branchio-oculo-facial
syndrome and inner ear malformation in a deaf child. Am. J. Med.
Genet. 149A: 427-430, 2009.

18. Warren, G.; Gordon, M.; Siracusa, L. D.; Buchberg, A. M.; Williams,
T.: Physical and genetic localization of the gene encoding the AP-2
transcription factor to mouse chromosome 13. Genomics 31: 234-237,
1996.

19. Williams, T.; Admon, A.; Luscher, B.; Tjian, R.: Cloning and
expression of AP-2, a cell-type-specific transcription factor that
activates inducible enhancer elements. Genes Dev. 2: 1557-1569,
1988.

20. Williamson, J. A.; Bosher, J. M.; Skinner, A.; Sheer, D.; Williams,
T.; Hurst, H. C.: Chromosomal mapping of the human and mouse homologues
of two new members of the AP-2 family of transcription factors. Genomics 35:
262-264, 1996.

21. Zarelli, V. E.; Dawid, I. B.: Inhibition of neural crest formation
by Kctd15 involves regulation of transcription factor AP-2. Proc.
Nat. Acad. Sci. 110: 2870-2875, 2013.

22. Zhang, J.; Hagopian-Donaldson, S.; Serbedzija, G.; Elsemore, J.;
Plehn-Dujowich, D.; McMahon, A. P.; Flavell, R. A.; Williams, T.:
Neural tube, skeletal and body wall defects in mice lacking transcription
factor AP-2. Nature 381: 238-241, 1996.

23. Zhu, C.-H.; Huang, Y.; Broman, M. T.; Domann, F. E.: Expression
of AP-2-alpha in SV40 immortalized human lung fibroblasts is associated
with a distinct pattern of cytosine methylation in the AP-2-alpha
promoter. Biochim. Biophys. Acta 1519: 85-91, 2001.

*FIELD* CN
Ada Hamosh - updated: 12/05/2013
Patricia A. Hartz - updated: 5/20/2013
George E. Tiller - updated: 12/1/2011
Marla J. F. O'Neill - updated: 10/19/2011
Marla J. F. O'Neill - updated: 12/1/2010
Marla J. F. O'Neill - updated: 8/27/2010
Marla J. F. O'Neill - updated: 8/25/2010
George E. Tiller - updated: 11/18/2008
Marla J. F. O'Neill - updated: 6/10/2008
John A. Phillips, III - updated: 8/6/2004
Patricia A. Hartz - updated: 1/27/2003
Victor A. McKusick - updated: 1/4/2002
Michael J. Wright - updated: 12/16/1999
Victor A. McKusick - updated: 3/3/1998
Alan F. Scott - updated: 1/3/1997

*FIELD* CD
Victor A. McKusick: 2/28/1992

*FIELD* ED
alopez: 12/05/2013
mgross: 5/20/2013
terry: 12/21/2012
alopez: 12/5/2011
terry: 12/1/2011
terry: 10/19/2011
wwang: 12/2/2010
terry: 12/1/2010
wwang: 9/1/2010
terry: 8/27/2010
wwang: 8/26/2010
terry: 8/25/2010
mgross: 1/19/2010
terry: 1/7/2010
carol: 12/14/2009
alopez: 2/27/2009
wwang: 11/18/2008
carol: 6/11/2008
terry: 6/10/2008
alopez: 8/6/2004
mgross: 1/30/2003
terry: 1/27/2003
carol: 7/8/2002
mcapotos: 1/9/2002
terry: 1/4/2002
alopez: 12/16/1999
dkim: 9/11/1998
dkim: 7/17/1998
alopez: 3/23/1998
terry: 3/3/1998
jenny: 1/7/1997
mark: 1/3/1997
terry: 1/2/1997
mark: 3/29/1996
mark: 3/18/1996
terry: 3/6/1996
jason: 6/28/1994
supermim: 3/16/1992
carol: 2/28/1992

MIM 113620
*RECORD*
*FIELD* NO
113620
*FIELD* TI
#113620 BRANCHIOOCULOFACIAL SYNDROME; BOFS
;;BOF SYNDROME;;
BRANCHIAL CLEFTS WITH CHARACTERISTIC FACIES, GROWTH RETARDATION, IMPERFORATE
read moreNASOLACRIMAL DUCT, AND PREMATURE AGING;;
HEMANGIOMATOUS BRANCHIAL CLEFTS-LIP PSEUDOCLEFT SYNDROME;;
LIP PSEUDOCLEFT-HEMANGIOMATOUS BRANCHIAL CYST SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
branchiooculofacial syndrome is caused by heterozygous mutation in the
TFAP2A gene (107580).

DESCRIPTION

Branchiooculofacial syndrome (BOFS) is characterized by branchial cleft
sinus defects, ocular anomalies such as microphthalmia and lacrimal duct
obstruction, a dysmorphic facial appearance including cleft or
pseudocleft lip/palate, and autosomal dominant inheritance. Although
anomalies of the external and middle ear frequently cause conductive
hearing loss in BOFS, severe to profound sensorineural hearing loss due
to inner ear anomalies has rarely been reported (summary by Tekin et
al., 2009).

See also chromosome 6pter-p24 deletion syndrome (612582) for a similar
phenotype, which lies telomeric to the TFAP2A gene.

CLINICAL FEATURES

Lee et al. (1982) described a 38-year-old woman and her 8-year-old son
who had low birth weight for dates and retarded postnatal growth,
bilateral branchial cleft sinuses, congenital strabismus, obstructed
nasolacrimal ducts, broad nasal bridge, protruding upper lip, and carp
mouth. Graying of the mother's hair occurred at age 18. Intelligence was
normal. The same disorder may have been reported by Hall et al. (1983)
and Fujimoto et al. (1987). Hall et al. (1983) described 2 unrelated
children (1 male, 1 female) with hemangiomatous branchial clefts and
pseudocleft of the upper lip (resembling a surgically repaired cleft or
a fused cleft). They found reports of 2 additional patients who, they
suspected, also represented sporadic cases of this syndrome. In several
persons in 3 families, Fujimoto et al. (1987) observed an autosomal
dominant disorder of abnormal upper lip, which resembled a poorly
repaired median cleft lip, malformed nose with broad bridge and
flattened tip, lacrimal duct obstruction, malformed ears, and branchial
cleft sinuses and/or linear skin lesions behind the ears. In each of the
3 families an affected parent had at least 1 affected child, and
father-to-son transmission was observed in 1. Other anomalies included
coloboma, microphthalmia, auricular pits, lip pits, highly arched
palate, dental anomalies, and subcutaneous cysts of the scalp. Premature
graying of hair occurred in affected adults. The abnormality of the
upper lip might be described as an unusually broad and prominent
philtrum.

Mazzone et al. (1992) reported a patient who, in addition to typical
features of BOFS, had partial agenesis of the cerebellar vermis. Lin et
al. (1992) concluded that the father and son reported by Legius et al.
(1990) had the BOF syndrome and that this additional finding of
male-to-male transmission confirmed autosomal dominant inheritance.
Fielding and Fryer (1992) described 2 sibs with this syndrome, each of
whom also had orbital hemangiomatous cysts. Both parents were clinically
normal and unrelated. Thus this may have represented an autosomal
recessive form of the disorder or germline mosaicism for the dominant
gene. Schmerler et al. (1992) reviewed the development of an affected
child over a 12-year period of observation. Normal intelligence, regular
class placement, hypernasal speech, and continued growth along the third
centile were noted. The infant had been referred at the age of 5 months
for evaluation of his facial appearance and 'burn-like' lesions behind
both ears. McCool and Weaver (1994) observed the BOF syndrome in a
mother and her son who lacked the ocular and branchial abnormalities but
had bilateral supraauricular sinuses and hearing loss. The son had
bilateral cleft lip and right alveolar cleft; the mother had asymmetric
nostrils and upper lip. The supraauricular sinuses were thought to
represent persistence of the otic vesicle sinus tract.

Lin et al. (1995) described 15 new cases of the BOF syndrome and
reviewed previously reported cases (28 with typical and 5 with atypical
manifestations) in detail. Postauricular cervical branchial defects were
found in 40 of 43 patients, and supraauricular defects were found in 6.
Pathologic findings of the excised branchial defects showed thymic
remnants in several cases. Colobomata were found in 16 of 35 patients,
cataracts in 8 of 33, deafness in 14 of 38, scalp cysts in 4 of 38, and
premature graying of hair in 9 of 38. Pseudoclefts were observed in 23
patients, and cleft lip and/or palate in 20. Urologic examination of 19
patients revealed kidney abnormalities (agenesis, cysts, hydronephrosis)
in 7. Autosomal dominant inheritance of the BOF syndrome is supported by
a 3-generation German family, 2 instances of father-to-son transmission,
and 7 other parent-offspring families (Fujimoto et al., 1987; Lin et
al., 1995).

Richardson et al. (1996) described a boy with cleft lip and palate,
microphthalmos, colobomata of optic nerves and irides, and cystic
dysplasia of the left kidney. His mother had similar ocular
abnormalities (plus polycoria), obstruction of nasolacrimal ducts, bifid
nasal tip, abnormal philtrum, hypodontia, and premature graying of the
hair. His maternal grandmother had the same facial defects and
nasolacrimal duct obstruction, but normal eyes. The spectrum of
abnormalities in this family fits the BOF syndrome, although cervical
hemangiomata or branchial sinuses were not found in affected persons in
this family.

McGaughran (2001) described a 1-year-old male with BOF syndrome together
with preaxial polydactyly and a white forelock at birth. The author
stated that this was only the second case in which preaxial polydactyly
had been described in the branchiooculofacial syndrome.

Demirci et al. (2005) reported the ocular manifestations of BOF syndrome
in a 10-year-old girl who had undergone excision of an orbital dermoid
cyst and branchial cleft fistula at age 4 years. At age 10, she had
sinus tracts on each side of the nose, connecting the lacrimal sac to
the skin. In addition, she had an iris pigment epithelial cyst in one
eye and a combined hamartoma of the retina and retinal pigment
epithelium in the other.

Although BOF syndrome and branchiootorenal (BOR) syndrome (113650) are
sufficiently distinctive that they should not be confused, both can be
associated with nasolacrimal duct stenosis, deafness, prehelical pits,
malformed pinna, and renal anomalies. Furthermore, Legius et al. (1990)
reported father and son with features of both conditions. In light of
these issues, Lin et al. (2000) performed a mutation search of the EYA1
gene in 5 BOF syndrome patients and found no EYA1 mutations, suggesting
that BOF syndrome is not allelic to the BOR syndrome. Lin et al. (2000)
emphasized that the unusual areas of thin, erythematous wrinkled skin of
the neck or infra/supraauricular region of BOF syndrome differ from the
discrete cervical pits, cysts, and fistulas of the BOR syndrome.

Tekin et al. (2009) reported a 4-year-old Turkish girl who was diagnosed
with bilateral profound sensorineural hearing loss at 1 year of age, in
whom temporal bone CT scan revealed bilateral cochlear dysplasia,
enlarged vestibule, and enlarged vestibular aqueduct; she underwent
cochlear implantation. In addition, she was diagnosed with right
multicystic dysplastic kidney and underwent unilateral nephrectomy. At 4
years of age, she had dolicocephaly, broad nasal bridge, upslanting
palpebral fissures, bilateral pseudoclefts on philtrum, low-set
posteriorly rotated ears, bilateral scars from skin defects in the
supraauricular region, 2 pits in the suprasternal notch, and bilateral
accessory nipples. Ophthalmologic examination was normal.

Stoetzel et al. (2009) studied a 3-generation family in which the
proband, his father, and his paternal grandmother had BOFS and a
heterozygous missense mutation in the TFAP2A gene. CT scan of the
temporal bone in the affected individuals showed consistent stenosis of
the round window, stenosis of the oval window, malformations of the
stapes, hypoplasia of the long process of the incus, normal cochlea, and
normal internal auditory meatus. Stoetzel et al. (2009) noted that major
differences on CT scan between BOFS and BOR syndrome, particularly of
the cochlea and internal auditory meatus canals, which are generally
normal in BOFS but always abnormal in BOR syndrome, could help
distinguish the 2 phenotypes.

CYTOGENETICS

Davies et al. (1999) reported a child with microphthalmia and corneal
clouding and a number of other dysmorphic features, including
hypertelorism, micrognathia, dysplastic ears, thin limbs, and congenital
cardiac defects. This child had an interstitial deletion of chromosome
6p25-p24 that did not include the FOXC1 gene (601090) but did include
the TFAP2A gene. Davies et al. (1999) suggested that there is an
additional locus within chromosome 6p25-p24 involved in anterior eye
chamber development and that AP2-alpha is a candidate gene.

MOLECULAR GENETICS

Milunsky et al. (2008) performed genomewide microarray analysis in a
mother and son with BOF syndrome and detected a 3.2-Mb deletion at
chromosome 6p24.3. Sequencing of candidate genes in that region in 4
additional unrelated BOFS patients, 2 of whom had previously been
studied by Lin et al. (2000), revealed 4 different de novo missense
mutations in a conserved region of the TFAP2A gene (see, e.g.,
107580.0001 and 107580.0002) that were not found in more than 300
controls. Milunsky et al. (2008) noted that although the affected mother
and son did not have overt cleft lip and palate, the boy did have an
abnormally short philtrum and bilaterally notched vermilion-mucosa
border, which are on the spectrum of microform cleft lip in BOFS. The
authors stated that their 'patient 5' was the first BOFS patient to be
reported with medulloblastoma.

Gestri et al. (2009) sequenced the TFAP2A gene in 37 patients with
developmental eye defects plus variable defects associated with BOFS and
identified 2 heterozygous mutations in 2 patients (107580.0003 and
107580.0004, respectively). In addition, multiplex ligation-dependent
probe amplification (MPLA) revealed a heterozygous deletion on
chromosome 6p24.3, encompassing TFAP2A and an adjacent predicted gene,
C6ORF218, in 2 sibs and their father from the family previously reported
by Fielding and Fryer (1992). The father, who was originally described
as unaffected, was found to exhibit mild, classic features of BOFS,
including prominent philtrum, bilateral 2/3 partial syndactyly of the
toes, bilateral malformed pinnae, and premature aging changes. He also
showed subtle ocular changes, with normal anterior segments bilaterally
but a dysplastic right optic disc with an unusual vessel pattern and
mild dysplasia of the left disc.

In a 4-year-old Turkish girl with profound bilateral sensorineural
hearing loss and features of BOFS, Tekin et al. (2009) identified a
heterozygous deletion/insertion mutation in the TFAP2A gene
(107580.0005).

In 2 families with BOFS, 1 of which was originally reported by Lin et
al. (1995), and 3 sporadic patients with BOFS, Reiber et al. (2010)
identified heterozygous mutations in the TFAP2A gene (see, e.g.,
107580.0001 and 107580.0006-107580.0007). Reiber et al. (2010) stated
that 1 of the sporadic patients studied by Reiber et al. (2010)
designated patient 'SP2,' had been previously reported by Bennaceur et
al. (1998) as 'patient 2.' Patient SP2 was not blind and did not have
severe deafness, but did display severe mental retardation. Reiber et
al. (2010) suggested that her developmental disability, which was not
due to a dual sensory handicap of blindness and deafness, might be part
of the spectrum of BOFS.

*FIELD* SA
Legius and Fryns (1992)
*FIELD* RF
1. Bennaceur, S.; Buisson, T.; Bertolus, C.; Couly, G.: Branchio-oculo-facial
syndrome with cleft lip and bilateral dermal thymus. Cleft Palate
Craniofac. J. 35: 454-459, 1998.

2. Davies, A. F.; Mirza, G.; Sekhon, G.; Turnpenny, P.; Leroy, F.;
Speleman, F.; Law, C.; van Regemorter, N.; Vamos, E.; Flinter, F.;
Ragoussis, J.: Delineation of two distinct 6p deletion syndromes. Hum.
Genet. 104: 64-72, 1999.

3. Demirci, H.; Shields, C. L.; Shields, J. A.: New ophthalmic manifestations
of branchio-oculo-facial syndrome. Am. J. Ophthal. 139: 362-364,
2005.

4. Fielding, D. W.; Fryer, A. E.: Recurrence of orbital cysts in
the branchio-oculo-facial syndrome. J. Med. Genet. 29: 430-431,
1992.

5. Fujimoto, A.; Lipson, M.; Lacro, R. V.; Shinno, N. W.; Boelter,
W. D.; Jones, K. L.; Wilson, M. G.: New autosomal dominant branchio-oculo-facial
syndrome. Am. J. Med. Genet. 27: 943-951, 1987.

6. Gestri, G.; Osborne, R. J.; Wyatt, A. W.; Gerrelli, D.; Gribble,
S.; Stewart, H.; Fryer, A.; Bunyan, D. J.; Prescott, K.; Collin, J.
R. O.; Fitzgerald, T.; Robinson, D.; Carter, N. P.; Wilson, S. W.;
Ragge, N. K.: Reduced TFAP2A function causes variable optic fissure
closure and retinal defects and sensitizes eye development to mutations
in other morphogenetic regulators. Hum. Genet. 126: 791-803, 2009.

7. Hall, B. D.; deLorimier, A.; Foster, L. H.: A new syndrome of
hemangiomatous branchial clefts, lip pseudoclefts, and unusual facial
appearance. Am. J. Med. Genet. 14: 135-138, 1983.

8. Lee, W. K.; Root, A. W.; Fenske, N.: Bilateral branchial cleft
sinuses associated with intrauterine and postnatal growth retardation,
premature aging, and unusual facial appearance: a new syndrome with
dominant transmission. Am. J. Med. Genet. 11: 345-352, 1982.

9. Legius, E.; Fryns, J.-P.: Reply to Dr. Lin. (Letter) Clin. Genet. 41:
223 only, 1992.

10. Legius, E.; Fryns, J. P.; Van Den Berghe, H.: Dominant branchial
cleft syndrome with characteristics of both branchio-oto-renal and
branchio-oculo-facial syndrome. Clin. Genet. 37: 347-350, 1990.

11. Lin, A. E.; Doherty, R.; Lea, D.: Branchio-oculo-facial and branchio-oto-renal
syndromes are distinct entities. (Letter) Clin. Genet. 41: 221-222,
1992.

12. Lin, A. E.; Gorlin, R. J.; Lurie, I. W.; Brunner, H. G.; van der
Burgt, I.; Naumchik, I. V.; Rumyantseva, N. V.; Stengel-Rutkowski,
S.; Rosenbaum, K.; Meinecke, P.; Muller, D.: Further delineation
of the branchio-oculo-facial syndrome. Am. J. Med. Genet. 56: 42-59,
1995.

13. Lin, A. E.; Semina, E. V.; Daack-Hirsch, S.; Roeder, E. R.; Curry,
C. J. R.; Rosenbaum, K.; Weaver, D. D.; Murray, J. C.: Exclusion
of the branchio-oto-renal syndrome locus (EYA1) from patients with
branchio-oculo-facial syndrome. Am. J. Med. Genet. 91: 387-390,
2000. Note: Erratum: Am. J. Med. Genet. 93: 169 only, 2000.

14. Mazzone, D.; Milana, A.; Carpinato, C.: Branchio-oculo-facial
syndrome: report of a new case with agenesis of cerebellar vermis. Europ.
J. Pediat. 151: 312 only, 1992.

15. McCool, M.; Weaver, D. D.: Branchio-oculo-facial syndrome: broadening
the spectrum. Am. J. Med. Genet. 49: 414-421, 1994.

16. McGaughran, J.: Another case of preaxial polydactyly and white
forelock in branchio-oculo-facial syndrome. Clin. Dysmorph. 10:
67-68, 2001.

17. Milunsky, J. M.; Maher, T. A.; Zhao, G.; Roberts, A. E.; Stalker,
H. J.; Zori, R. T.; Burch, M. N.; Clemens, M.; Mulliken, J. B.; Smith,
R.; Lin, A. E.: TFAP2A mutations result in branchio-oculo-facial
syndrome. Am. J. Hum. Genet. 82: 1171-1177, 2008. Note: Erratum:
Am. J. Hum. Genet. 84: 301 only, 2009.

18. Reiber, J.; Sznajer, Y.; Guillen Posteguillo, E.; Muller, D.;
Lyonnet, S.; Baumann, C.; Just, W.: Additional clinical and molecular
analyses of TFAP2A in patients with the branchio-oculo-facial syndrome. Am.
J. Med. Genet. 152A: 994-999, 2010.

19. Reiber, J.; Sznajer, Y.; Posteguillo, E. G.; Muller, D.; Lyonnet,
S.; Baumann, C.; Just, W.: Additonal clinical and molecular analyses
of TFAP2A in patients with the branchio-oculo-facial syndrome: previously
reported patient. (Letter) Am. J. Med. Genet. 152A: 2143 only, 2010.

20. Richardson, E.; Davison, C.; Moore, A.: Colobomatous microphthalmia
with midfacial clefting: part of the spectrum of branchio-oculo-facial
syndrome? Ophthal. Genet. 17: 59-65, 1996.

21. Schmerler, S.; Kushnick, T.; Desposito, F.: Long-term evaluation
of a child with the branchio-oculo-facial syndrome. Am. J. Med. Genet. 44:
177-178, 1992.

22. Stoetzel, C.; Riehm, S.; Bennouna Greene, V.; Pelletier, V.; Vigneron,
J.; Leheup, B.; Marion, V.; Helle, S.; Danse, J. M.; Thibault, C.;
Moulinier, L.; Veillon, F.; Dollfus, H.: Confirmation of TFAP2A gene
involvement in branchio-oculo-facial syndrome (BOFS) and report of
temporal bone anomalies. Am. J. Med. Genet. 149A: 2141-2146, 2009.

23. Tekin, M.; Sirmaci, A.; Yuksel-Konuk, B.; Fitoz, S.; Sennaroglu,
L.: A complex TFAP2A allele is associated with branchio-oculo-facial
syndrome and inner ear malformation in a deaf child. Am. J. Med.
Genet. 149A: 427-430, 2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Prenatal growth deficiency (27%);
Postnatal growth deficiency (50%)

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
Small forehead;
[Ears];
Low-set ears;
Posteriorly rotated ears;
Hypoplastic superior helix;
Microtia;
Posterior auricular pit;
Preauricular pit;
Overfolded ears;
Supraauricular sinuses;
Conductive hearing loss;
[Eyes];
Lacrimal sac fistula;
Orbital dermoid cyst;
Iris pigment epithelial cyst;
Combined hamartoma of the retina and retinal pigment epithelium;
Upslanting palpebral fissures;
Telecanthus;
Hypertelorism;
Ptosis;
Lacrimal duct obstruction;
Iris coloboma;
Retinal coloboma;
Microphthalmia;
Anophthalmia;
Myopia;
Cataract;
Strabismus;
[Nose];
Broad nasal tip;
Divided nasal tip;
Depressed nasal bridge;
Short nasal septum;
[Mouth];
Pseudocleft;
Incomplete/complete cleft lip;
Cleft palate;
Lip pits;
[Teeth];
Dental abnormalities;
[Neck];
Branchial anomalies

CHEST:
[Breasts];
Widely spaced nipples;
Supernumerary nipples

GENITOURINARY:
[Kidneys];
Renal agenesis;
Cystic kidney

SKELETAL:
[Skull];
Malar hypoplasia;
Mastoid hypoplasia with absence of air cells;
Fusion of middle ear ossicles;
[Spine];
Kyphosis;
Lordosis;
[Hands];
Polydactyly;
Clinodactyly;
Single transverse palmar crease;
Hypoplastic thumbs

SKIN, NAILS, HAIR:
[Skin];
Aplasia cutis congenita;
Subcutaneous scalp cysts;
Hemangiomatous branchial clefts (extend along sternocleidomastoid
muscle);
Single transverse palmar crease;
[Nails];
Hypoplastic fingernails;
[Hair];
Premature graying of hair

NEUROLOGIC:
[Central nervous system];
Mild mental retardation;
Agenesis of cerebellar vermis

VOICE:
Hypernasal speech

IMMUNOLOGY:
Ectopic thymus

MISCELLANEOUS:
Normal intelligence in majority

MOLECULAR BASIS:
Caused by mutation in the transcription factor AP2-alpha gene (TFAP2A,
107580.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 1/28/2009
Jane Kelly - updated: 12/23/2005
Kelly A. Przylepa - revised: 3/1/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 02/09/2011
joanna: 1/28/2009
joanna: 12/23/2005
joanna: 2/1/2005
joanna: 3/30/2004
joanna: 3/1/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 3/4/2011
Marla J. F. O'Neill - updated: 2/3/2011
Marla J. F. O'Neill - updated: 12/1/2010
Marla J. F. O'Neill - updated: 8/27/2010
Marla J. F. O'Neill - updated: 8/25/2010
Marla J. F. O'Neill - updated: 10/12/2009
Marla J. F. O'Neill - updated: 6/10/2008
Jane Kelly - updated: 11/17/2005
Ada Hamosh - updated: 2/1/2001
Victor A. McKusick - updated: 4/19/2000
Iosif W. Lurie - updated: 12/4/1996
Iosif W. Lurie - updated: 7/18/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/21/2012
terry: 3/10/2011
wwang: 3/7/2011
terry: 3/4/2011
wwang: 2/8/2011
terry: 2/3/2011
wwang: 12/2/2010
terry: 12/1/2010
wwang: 9/1/2010
terry: 8/27/2010
wwang: 8/26/2010
terry: 8/25/2010
wwang: 10/12/2009
alopez: 2/27/2009
carol: 6/11/2008
terry: 6/10/2008
carol: 11/17/2005
mgross: 3/17/2004
mcapotos: 2/8/2001
terry: 2/1/2001
carol: 4/19/2000
terry: 4/19/2000
jamie: 12/6/1996
jamie: 12/4/1996
carol: 7/18/1996
terry: 5/13/1994
mimadm: 4/9/1994
carol: 3/7/1994
carol: 10/9/1992
carol: 7/1/1992
carol: 6/8/1992