RBCC Red Blood Cell Collection

JUP (CTNNG, DP3) [Confidence: low (only semi-automatic identification from reviews)]
Junction plakoglobin (Catenin gamma; Desmoplakin III; Desmoplakin-3)

UniProt P14923
ID PLAK_HUMAN Reviewed; 745 AA.
AC P14923; Q15093; Q15151; Q7L3S5; Q86W21; Q9BWC4; Q9HCX9;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 02-SEP-2008, sequence version 3.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Junction plakoglobin;
DE AltName: Full=Catenin gamma;
DE AltName: Full=Desmoplakin III;
DE AltName: Full=Desmoplakin-3;
GN Name=JUP; Synonyms=CTNNG, DP3;
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].
RX PubMed=2726765; DOI=10.1073/pnas.86.11.4027;
RA Franke W.W., Goldschmidt M.D., Zimbelmann R., Mueller H.M.,
RA Schiller D.L., Cowin P.;
RT "Molecular cloning and amino acid sequence of human plakoglobin, the
RT common junctional plaque protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:4027-4031(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Zimbelmann R.;
RL Submitted (DEC-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11016852; DOI=10.1034/j.1600-0625.2000.009005323.x;
RA Whittock N.V., Eady R.A.J., McGrath J.A.;
RT "Genomic organization and amplification of the human plakoglobin gene
RT (JUP).";
RL Exp. Dermatol. 9:323-326(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT LEU-697.
RC TISSUE=Epidermal carcinoma;
RA Liang X.-J., Gottesman M.M.;
RT "Homo sapiens gamma-catenin mRNA from human KB epidermoid
RT adenocarcinoma cells.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT LEU-697.
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-697.
RC TISSUE=Lung, and Placenta;
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 [8]
RP PROTEIN SEQUENCE OF 1-12; 116-142; 150-172; 177-203; 217-233; 273-279;
RP 304-320; 327-333; 368-394; 427-460; 466-533; 583-602; 638-661 AND
RP 664-674, ACETYLATION AT MET-1, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma, and Lung carcinoma;
RA Bienvenut W.V., Vousden K.H., Lukashchuk N., Calvo F., Kolch W.;
RL Submitted (MAR-2008) to UniProtKB.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 634-745, VARIANT LEU-697, AND
RP INVOLVEMENT IN NAXOS DISEASE.
RC TISSUE=Leukocyte;
RX PubMed=10902626; DOI=10.1016/S0140-6736(00)02379-5;
RA McKoy G., Protonotarios N., Crosby A., Tsatsopoulou A.,
RA Anastasakis A., Coonar A., Norman M., Baboonian C., Jeffery S.,
RA McKenna W.J.;
RT "Identification of a deletion in plakoglobin in arrhythmogenic right
RT ventricular cardiomyopathy with palmoplantar keratoderma and woolly
RT hair (Naxos disease).";
RL Lancet 355:2119-2124(2000).
RN [10]
RP IDENTIFICATION IN AN E-CADHERIN/CATENIN ADHESION COMPLEX.
RX PubMed=7982500; DOI=10.1016/0014-5793(94)01205-9;
RA Butz S., Kemler R.;
RT "Distinct cadherin-catenin complexes in Ca(2+)-dependent cell-cell
RT adhesion.";
RL FEBS Lett. 355:195-200(1994).
RN [11]
RP DOMAIN, AND INTERACTION WITH CTNNA1; DSC1 AND DSG1.
RX PubMed=8631907; DOI=10.1074/jbc.271.18.10904;
RA Witcher L.L., Collins R., Puttagunta S., Mechanic S.E., Munson M.,
RA Gumbiner B., Cowin P.;
RT "Desmosomal cadherin binding domains of plakoglobin.";
RL J. Biol. Chem. 271:10904-10909(1996).
RN [12]
RP INTERACTION WITH MUC1.
RX PubMed=9139698; DOI=10.1074/jbc.272.19.12492;
RA Yamamoto M., Bharti A., Li Y., Kufe D.;
RT "Interaction of the DF3/MUC1 breast carcinoma-associated antigen and
RT beta-catenin in cell adhesion.";
RL J. Biol. Chem. 272:12492-12494(1997).
RN [13]
RP INTERACTION WITH CTNNA1.
RX PubMed=9152027;
RA Nieset J.E., Redfield A.R., Jin F., Knudsen K.A., Johnson K.R.,
RA Wheelock M.J.;
RT "Characterization of the interactions of alpha-catenin with alpha-
RT actinin and beta-catenin/plakoglobin.";
RL J. Cell Sci. 110:1013-1022(1997).
RN [14]
RP INTERACTION WITH PTPRJ.
RX PubMed=12370829; DOI=10.1038/sj.onc.1205858;
RA Holsinger L.J., Ward K., Duffield B., Zachwieja J., Jallal B.;
RT "The transmembrane receptor protein tyrosine phosphatase DEP1
RT interacts with p120(ctn).";
RL Oncogene 21:7067-7076(2002).
RN [15]
RP GLYCOSYLATION AT THR-14, AND MUTAGENESIS OF THR-14; THR-19; THR-21;
RP SER-24; SER-28 AND THR-32.
RX PubMed=12847106; DOI=10.1074/jbc.M301346200;
RA Hatsell S., Medina L., Merola J., Haltiwanger R., Cowin P.;
RT "Plakoglobin is O-glycosylated close to the N-terminal destruction
RT box.";
RL J. Biol. Chem. 278:37745-37752(2003).
RN [16]
RP PHOSPHORYLATION BY FER.
RX PubMed=14517306; DOI=10.1128/MCB.23.20.7391-7402.2003;
RA Miravet S., Piedra J., Castano J., Raurell I., Franci C., Dunach M.,
RA Garcia de Herreros A.;
RT "Tyrosine phosphorylation of plakoglobin causes contrary effects on
RT its association with desmosomes and adherens junction components and
RT modulates beta-catenin-mediated transcription.";
RL Mol. Cell. Biol. 23:7391-7402(2003).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-182 AND SER-665, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-665, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP INTERACTION WITH DSC2.
RX PubMed=21062920; DOI=10.1093/cvr/cvq353;
RA Gehmlich K., Syrris P., Peskett E., Evans A., Ehler E., Asimaki A.,
RA Anastasakis A., Tsatsopoulou A., Vouliotis A.I., Stefanadis C.,
RA Saffitz J.E., Protonotarios N., McKenna W.J.;
RT "Mechanistic insights into arrhythmogenic right ventricular
RT cardiomyopathy caused by desmocollin-2 mutations.";
RL Cardiovasc. Res. 90:77-87(2011).
RN [21]
RP INTERACTION WITH PKP2, AND SUBCELLULAR LOCATION.
RX PubMed=22781308; DOI=10.1161/CIRCGENETICS.111.961854;
RA Kirchner F., Schuetz A., Boldt L.H., Martens K., Dittmar G.,
RA Haverkamp W., Thierfelder L., Heinemann U., Gerull B.;
RT "Molecular insights into arrhythmogenic right ventricular
RT cardiomyopathy caused by plakophilin-2 missense mutations.";
RL Circ. Cardiovasc. Genet. 5:400-411(2012).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 124-676 IN COMPLEX WITH
RP PHOSPHORYLATED MOUSE E-CADHERIN, DOMAIN ARM REPEATS, AND INTERACTION
RP WITH DSC1 AND DSG1.
RX PubMed=19759396; DOI=10.1074/jbc.M109.047928;
RA Choi H.J., Gross J.C., Pokutta S., Weis W.I.;
RT "Interactions of plakoglobin and beta-catenin with desmosomal
RT cadherins: basis of selective exclusion of alpha- and beta-catenin
RT from desmosomes.";
RL J. Biol. Chem. 284:31776-31788(2009).
RN [23]
RP VARIANT ARVD12 SER-39 INS, AND CHARACTERIZATION OF VARIANT ARVD12
RP SER-39 INS.
RX PubMed=17924338; DOI=10.1086/521633;
RA Asimaki A., Syrris P., Wichter T., Matthias P., Saffitz J.E.,
RA McKenna W.J.;
RT "A novel dominant mutation in plakoglobin causes arrhythmogenic right
RT ventricular cardiomyopathy.";
RL Am. J. Hum. Genet. 81:964-973(2007).
RN [24]
RP VARIANT ARVD12 ILE-19, AND VARIANTS HIS-142; ILE-648 AND LEU-697.
RX PubMed=20031617; DOI=10.1161/CIRCGENETICS.109.858217;
RA den Haan A.D., Tan B.Y., Zikusoka M.N., Llado L.I., Jain R., Daly A.,
RA Tichnell C., James C., Amat-Alarcon N., Abraham T., Russell S.D.,
RA Bluemke D.A., Calkins H., Dalal D., Judge D.P.;
RT "Comprehensive desmosome mutation analysis in North Americans with
RT arrhythmogenic right ventricular dysplasia/cardiomyopathy.";
RL Circ. Cardiovasc. Genet. 2:428-435(2009).
RN [25]
RP VARIANTS HIS-142 AND LEU-697.
RX PubMed=19863551; DOI=10.1111/j.1399-0004.2009.01282.x;
RA Barahona-Dussault C., Benito B., Campuzano O., Iglesias A.,
RA Leung T.L., Robb L., Talajic M., Brugada R.;
RT "Role of genetic testing in arrhythmogenic right ventricular
RT cardiomyopathy/dysplasia.";
RL Clin. Genet. 77:37-48(2010).
CC -!- FUNCTION: Common junctional plaque protein. The membrane-
CC associated plaques are architectural elements in an important
CC strategic position to influence the arrangement and function of
CC both the cytoskeleton and the cells within the tissue. The
CC presence of plakoglobin in both the desmosomes and in the
CC intermediate junctions suggests that it plays a central role in
CC the structure and function of submembranous plaques. Acts as a
CC substrate for VE-PTP and is required by it to stimulate VE-
CC cadherin function in endothelial cells. Can replace beta-catenin
CC in E-cadherin/catenin adhesion complexes which are proposed to
CC couple cadherins to the actin cytoskeleton (By similarity).
CC -!- SUBUNIT: Homodimer. Component of an E-cadherin/catenin adhesion
CC complex composed of at least E-cadherin/CDH1 and gamma-
CC catenin/JUP, and possibly alpha-catenin/CTNNA1; the complex is
CC located to adherens junctions. The stable association of CTNNA1 is
CC controversial as CTNNA1 was shown not to bind to F-actin when
CC assembled in the complex. Interacts with MUC1. Interacts with CAV1
CC (By similarity). Interacts with PTPRJ. Interacts with DSG1.
CC Interacts with DSC1 and DSC2. Interacts with PKP2.
CC -!- INTERACTION:
CC P16284:PECAM1; NbExp=7; IntAct=EBI-702484, EBI-716404;
CC P49768:PSEN1; NbExp=4; IntAct=EBI-702484, EBI-297277;
CC Q9NQB0:TCF7L2; NbExp=13; IntAct=EBI-702484, EBI-924724;
CC Q96HA8:WDYHV1; NbExp=3; IntAct=EBI-702484, EBI-741158;
CC -!- SUBCELLULAR LOCATION: Cell junction, adherens junction. Cell
CC junction, desmosome. Cytoplasm, cytoskeleton. Membrane; Peripheral
CC membrane protein. Note=Cytoplasmic in a soluble and membrane-
CC associated form.
CC -!- DOMAIN: The entire ARM repeats region mediates binding to CDH1/E-
CC cadherin. The N-terminus and first three ARM repeats are
CC sufficient for binding to DSG1. The N-terminus and first ARM
CC repeat are sufficient for association with CTNNA1. DSC1
CC association requires both ends of the ARM repeat region.
CC -!- PTM: May be phosphorylated by FER.
CC -!- DISEASE: Naxos disease (NXD) [MIM:601214]: An autosomal recessive
CC disorder characterized by the association of diffuse non-
CC epidermolytic palmoplantar keratoderma with woolly hair and
CC cardiac abnormalities such as dilated cardiomyopathy and
CC arrhythmogenic right ventricular dysplasia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Arrhythmogenic right ventricular dysplasia, familial, 12
CC (ARVD12) [MIM:611528]: A congenital heart disease characterized by
CC infiltration of adipose and fibrous tissue into the right
CC ventricle and loss of myocardial cells, resulting in ventricular
CC and supraventricular arrhythmias. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the beta-catenin family.
CC -!- SIMILARITY: Contains 12 ARM repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00441.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/JUP";
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DR EMBL; M23410; AAA64895.1; -; mRNA.
DR EMBL; Z68228; CAA92522.1; -; mRNA.
DR EMBL; AF306723; AAG16727.1; -; Genomic_DNA.
DR EMBL; AF233882; AAG16727.1; JOINED; Genomic_DNA.
DR EMBL; AY243535; AAO85780.1; -; mRNA.
DR EMBL; AC109319; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471152; EAW60762.1; -; Genomic_DNA.
DR EMBL; BC000441; AAH00441.2; ALT_INIT; mRNA.
DR EMBL; BC011865; AAH11865.1; -; mRNA.
DR EMBL; AJ249711; CAC04246.1; -; Genomic_DNA.
DR PIR; A32905; A32905.
DR RefSeq; NP_002221.1; NM_002230.2.
DR RefSeq; NP_068831.1; NM_021991.2.
DR RefSeq; XP_005257371.1; XM_005257314.1.
DR RefSeq; XP_005257372.1; XM_005257315.1.
DR RefSeq; XP_005257373.1; XM_005257316.1.
DR RefSeq; XP_005257374.1; XM_005257317.1.
DR RefSeq; XP_005257375.1; XM_005257318.1.
DR RefSeq; XP_005257376.1; XM_005257319.1.
DR RefSeq; XP_005257377.1; XM_005257320.1.
DR RefSeq; XP_005257378.1; XM_005257321.1.
DR RefSeq; XP_005277072.1; XM_005277015.1.
DR RefSeq; XP_005277073.1; XM_005277016.1.
DR RefSeq; XP_005277074.1; XM_005277017.1.
DR RefSeq; XP_005277075.1; XM_005277018.1.
DR RefSeq; XP_005277076.1; XM_005277019.1.
DR RefSeq; XP_005277077.1; XM_005277020.1.
DR RefSeq; XP_005277078.1; XM_005277021.1.
DR RefSeq; XP_005277079.1; XM_005277022.1.
DR UniGene; Hs.514174; -.
DR PDB; 3IFQ; X-ray; 2.80 A; A/B=124-676.
DR PDBsum; 3IFQ; -.
DR ProteinModelPortal; P14923; -.
DR SMR; P14923; 111-673.
DR IntAct; P14923; 33.
DR MINT; MINT-105053; -.
DR STRING; 9606.ENSP00000311113; -.
DR PhosphoSite; P14923; -.
DR DMDM; 205371866; -.
DR PaxDb; P14923; -.
DR PRIDE; P14923; -.
DR DNASU; 3728; -.
DR Ensembl; ENST00000310706; ENSP00000311113; ENSG00000173801.
DR Ensembl; ENST00000393930; ENSP00000377507; ENSG00000173801.
DR Ensembl; ENST00000393931; ENSP00000377508; ENSG00000173801.
DR Ensembl; ENST00000562805; ENSP00000456867; ENSG00000261577.
DR Ensembl; ENST00000565220; ENSP00000454630; ENSG00000261577.
DR Ensembl; ENST00000565780; ENSP00000457186; ENSG00000261577.
DR GeneID; 3728; -.
DR KEGG; hsa:3728; -.
DR UCSC; uc002hxq.2; human.
DR CTD; 3728; -.
DR GeneCards; GC17M039776; -.
DR HGNC; HGNC:6207; JUP.
DR HPA; CAB002139; -.
DR MIM; 173325; gene.
DR MIM; 601214; phenotype.
DR MIM; 611528; phenotype.
DR neXtProt; NX_P14923; -.
DR Orphanet; 293899; Familial isolated arrhythmogenic ventricular dysplasia, biventricular form.
DR Orphanet; 293888; Familial isolated arrhythmogenic ventricular dysplasia, left dominant form.
DR Orphanet; 293910; Familial isolated arrhythmogenic ventricular dysplasia, right dominant form.
DR Orphanet; 158687; Lethal acantholytic epidermolysis bullosa.
DR Orphanet; 34217; Naxos disease.
DR PharmGKB; PA30009; -.
DR eggNOG; NOG297695; -.
DR HOVERGEN; HBG000919; -.
DR InParanoid; P14923; -.
DR KO; K10056; -.
DR OMA; MNLIEQP; -.
DR PhylomeDB; P14923; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR SignaLink; P14923; -.
DR ChiTaRS; JUP; human.
DR EvolutionaryTrace; P14923; -.
DR GeneWiki; Plakoglobin; -.
DR GenomeRNAi; 3728; -.
DR NextBio; 14595; -.
DR PMAP-CutDB; P14923; -.
DR PRO; PR:P14923; -.
DR ArrayExpress; P14923; -.
DR Bgee; P14923; -.
DR CleanEx; HS_JUP; -.
DR Genevestigator; P14923; -.
DR GO; GO:0015629; C:actin cytoskeleton; IBA:RefGenome.
DR GO; GO:0016327; C:apicolateral plasma membrane; IEA:Ensembl.
DR GO; GO:0016323; C:basolateral plasma membrane; IBA:RefGenome.
DR GO; GO:0016342; C:catenin complex; IDA:BHF-UCL.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; ISS:BHF-UCL.
DR GO; GO:0030057; C:desmosome; IDA:BHF-UCL.
DR GO; GO:0005916; C:fascia adherens; IBA:RefGenome.
DR GO; GO:0071665; C:gamma-catenin-TCF7L2 complex; IDA:BHF-UCL.
DR GO; GO:0005882; C:intermediate filament; IEA:Ensembl.
DR GO; GO:0016328; C:lateral plasma membrane; IEA:Ensembl.
DR GO; GO:0032993; C:protein-DNA complex; IDA:BHF-UCL.
DR GO; GO:0030018; C:Z disc; IBA:RefGenome.
DR GO; GO:0005915; C:zonula adherens; ISS:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL.
DR GO; GO:0019901; F:protein kinase binding; IBA:RefGenome.
DR GO; GO:0005199; F:structural constituent of cell wall; IC:BHF-UCL.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:BHF-UCL.
DR GO; GO:0034332; P:adherens junction organization; TAS:Reactome.
DR GO; GO:0003181; P:atrioventricular valve morphogenesis; IBA:RefGenome.
DR GO; GO:0086069; P:bundle of His cell to Purkinje myocyte communication; IMP:BHF-UCL.
DR GO; GO:0016477; P:cell migration; IMP:BHF-UCL.
DR GO; GO:0000902; P:cell morphogenesis; IBA:RefGenome.
DR GO; GO:0071681; P:cellular response to indole-3-methanol; IDA:UniProtKB.
DR GO; GO:0007016; P:cytoskeletal anchoring at plasma membrane; NAS:BHF-UCL.
DR GO; GO:0002159; P:desmosome assembly; IDA:BHF-UCL.
DR GO; GO:0050982; P:detection of mechanical stimulus; IDA:BHF-UCL.
DR GO; GO:0007398; P:ectoderm development; IBA:RefGenome.
DR GO; GO:0071603; P:endothelial cell-cell adhesion; ISS:BHF-UCL.
DR GO; GO:0007369; P:gastrulation; IBA:RefGenome.
DR GO; GO:0016331; P:morphogenesis of embryonic epithelium; IBA:RefGenome.
DR GO; GO:0003136; P:negative regulation of heart induction by canonical Wnt receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0003308; P:negative regulation of Wnt receptor signaling pathway involved in heart development; IBA:RefGenome.
DR GO; GO:0007399; P:nervous system development; IBA:RefGenome.
DR GO; GO:0048599; P:oocyte development; IBA:RefGenome.
DR GO; GO:0090263; P:positive regulation of canonical Wnt receptor signaling pathway; IC:BHF-UCL.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0051091; P:positive regulation of sequence-specific DNA binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0042127; P:regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0086005; P:regulation of ventricular cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0043588; P:skin development; IBA:RefGenome.
DR Gene3D; 1.25.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000225; Armadillo.
DR InterPro; IPR013284; Beta-catenin.
DR Pfam; PF00514; Arm; 3.
DR PRINTS; PR01869; BCATNINFAMLY.
DR SMART; SM00185; ARM; 12.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50176; ARM_REPEAT; 9.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cardiomyopathy; Cell adhesion;
KW Cell junction; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Glycoprotein; Membrane;
KW Palmoplantar keratoderma; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat.
FT CHAIN 1 745 Junction plakoglobin.
FT /FTId=PRO_0000064278.
FT REPEAT 132 171 ARM 1.
FT REPEAT 172 215 ARM 2.
FT REPEAT 216 255 ARM 3.
FT REPEAT 258 297 ARM 4.
FT REPEAT 298 341 ARM 5.
FT REPEAT 342 381 ARM 6.
FT REPEAT 383 420 ARM 7.
FT REPEAT 423 464 ARM 8.
FT REPEAT 470 510 ARM 9.
FT REPEAT 512 551 ARM 10.
FT REPEAT 574 613 ARM 11.
FT REPEAT 615 661 ARM 12.
FT REGION 132 297 Interaction with DSC1 and DSG1.
FT REGION 574 661 Interaction with DSC1.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 182 182 Phosphoserine.
FT MOD_RES 665 665 Phosphoserine.
FT CARBOHYD 14 14 O-linked (GlcNAc).
FT VARIANT 19 19 T -> I (in ARVD12).
FT /FTId=VAR_065698.
FT VARIANT 39 39 S -> SS (in ARVD12; affects the structure
FT and distribution of mechanical and
FT electrical cell junctions).
FT /FTId=VAR_037803.
FT VARIANT 142 142 R -> H (in dbSNP:rs41283425).
FT /FTId=VAR_065699.
FT VARIANT 648 648 V -> I (in dbSNP:rs143043662).
FT /FTId=VAR_065700.
FT VARIANT 697 697 M -> L (in dbSNP:rs1126821).
FT /FTId=VAR_037804.
FT MUTAGEN 14 14 T->A: Abolishes glycosylation. Does not
FT affect binding to CDH1, DSC1 or DSG1.
FT MUTAGEN 19 19 T->A: Reduces glycosylation.
FT MUTAGEN 21 21 T->A: Does not affect glycosylation.
FT MUTAGEN 24 24 S->A: Does not affect glycosylation.
FT MUTAGEN 28 28 S->A: Does not affect glycosylation.
FT MUTAGEN 32 32 T->A: Does not affect glycosylation.
FT CONFLICT 91 91 P -> S (in Ref. 4; AAO85780).
FT CONFLICT 264 270 VRLADGL -> CAGRRA (in Ref. 1; AAA64895).
FT HELIX 127 131
FT HELIX 133 142
FT HELIX 144 151
FT HELIX 156 169
FT HELIX 173 180
FT HELIX 183 193
FT HELIX 199 212
FT HELIX 216 224
FT HELIX 227 233
FT HELIX 234 236
FT HELIX 240 256
FT HELIX 260 266
FT HELIX 269 272
FT HELIX 274 278
FT HELIX 282 296
FT HELIX 300 308
FT HELIX 311 321
FT HELIX 325 338
FT HELIX 344 350
FT HELIX 353 358
FT HELIX 359 362
FT HELIX 366 380
FT HELIX 390 397
FT TURN 398 401
FT HELIX 405 418
FT TURN 419 421
FT HELIX 423 429
FT TURN 430 433
FT HELIX 434 445
FT HELIX 449 462
FT STRAND 464 466
FT HELIX 469 477
FT TURN 478 480
FT HELIX 481 487
FT HELIX 488 490
FT HELIX 495 508
FT HELIX 512 514
FT HELIX 515 520
FT HELIX 523 543
FT HELIX 556 570
FT HELIX 574 582
FT HELIX 586 592
FT HELIX 598 611
FT HELIX 615 623
FT TURN 624 626
FT HELIX 627 633
FT HELIX 639 651
FT HELIX 662 667
SQ SEQUENCE 745 AA; 81745 MW; 3519A0973748BCF4 CRC64;
MEVMNLMEQP IKVTEWQQTY TYDSGIHSGA NTCVPSVSSK GIMEEDEACG RQYTLKKTTT
YTQGVPPSQG DLEYQMSTTA RAKRVREAMC PGVSGEDSSL LLATQVEGQA TNLQRLAEPS
QLLKSAIVHL INYQDDAELA TRALPELTKL LNDEDPVVVT KAAMIVNQLS KKEASRRALM
GSPQLVAAVV RTMQNTSDLD TARCTTSILH NLSHHREGLL AIFKSGGIPA LVRMLSSPVE
SVLFYAITTL HNLLLYQEGA KMAVRLADGL QKMVPLLNKN NPKFLAITTD CLQLLAYGNQ
ESKLIILANG GPQALVQIMR NYSYEKLLWT TSRVLKVLSV CPSNKPAIVE AGGMQALGKH
LTSNSPRLVQ NCLWTLRNLS DVATKQEGLE SVLKILVNQL SVDDVNVLTC ATGTLSNLTC
NNSKNKTLVT QNSGVEALIH AILRAGDKDD ITEPAVCALR HLTSRHPEAE MAQNSVRLNY
GIPAIVKLLN QPNQWPLVKA TIGLIRNLAL CPANHAPLQE AAVIPRLVQL LVKAHQDAQR
HVAAGTQQPY TDGVRMEEIV EGCTGALHIL ARDPMNRMEI FRLNTIPLFV QLLYSSVENI
QRVAAGVLCE LAQDKEAADA IDAEGASAPL MELLHSRNEG TATYAAAVLF RISEDKNPDY
RKRVSVELTN SLFKHDPAAW EAAQSMIPIN EPYGDDMDAT YRPMYSSDVP LDPLEMHMDM
DGDYPIDTYS DGLRPPYPTA DHMLA
//

MIM 173325
*RECORD*
*FIELD* NO
173325
*FIELD* TI
*173325 JUNCTION PLAKOGLOBIN; JUP
;;PLAKOGLOBIN; PKGB;;
DESMOPLAKIN III; DP III; DP3;;
read moreCATENIN, GAMMA
*FIELD* TX

CLONING

Plakoglobin is a major cytoplasmic protein that occurs in a soluble and
a membrane-associated form and is the only known constituent common to
the submembranous plaques of both kinds of adhering junctions, the
desmosomes and the intermediate junctions. It is a desmoplakin (see
125647) and is referred to as DP III. DP I and DP II are splice variants
of the same gene. Using a partial cDNA clone for bovine plakoglobin,
Franke et al. (1989) isolated cDNAs encoding human plakoglobin,
determined its nucleotide sequence, and deduced the complete amino acid
sequence. The polypeptide encoded by the cDNA was synthesized by in
vitro transcription and translation and identified by its comigration
with authentic plakoglobin in 2-dimensional gel electrophoresis. The
protein, which has 744 amino acids and a molecular weight of 81,750 Da,
is highly conserved between human and bovine tissues. Only one kind of
plakoglobin mRNA (3.4 kb) was found in most tissues, but an additional
mRNA (3.7 kb) was detected in certain human tumor cell lines.

GENE FUNCTION

Plakoglobin associates with the cytoplasmic region of desmoglein I
(125670), one of the transmembrane desmosomal proteins (Mathur et al.,
1994). It also is a component of the cadherin (see 192090)-catenin
complex, which is predominantly localized where actin filaments anchor
in adherens junctions of epithelial cells (Knudsen and Wheelock, 1992).
Aberle et al. (1995) stated that catenins are of central importance for
cadherin function in that they mediate the connection of cadherins to
actin filaments and are part of a higher order submembranous network by
which cadherins are linked to other transmembrane and peripheral
cytoplasmic proteins. Interaction of the cadherin-catenin complex with
epidermal growth factor receptor (EGFR; 131550) and the finding that
beta-catenin (CTNNB1; 116806) and plakoglobin are substrates for
tyrosine phosphorylation following EGF stimulation of cells, together
with the finding that catenins are associated with the tumor suppressor
protein APC (611731), open the possibility that catenins are involved in
signaling pathways and tumorigenesis.

Beta-catenin and gamma-catenin, vertebrate homologs of Drosophila
armadillo, function in cell adhesion and the Wnt (e.g., WNT1; 164820)
signaling pathway. In colon and other cancers, mutations in the APC
tumor suppressor protein or beta-catenin's N terminus stabilize
beta-catenin, enhancing its ability to activate transcription of TCF
(e.g., TCF7; 189908)/LEF (e.g., LEF1; 153245) target genes. Beta- and
gamma-catenin have analogous structures and functions and like binding
to APC. Kolligs et al. (2000) reported that APC regulates both beta- and
gamma-catenin and gamma-catenin functions as an oncogene. In contrast to
beta-catenin, for which only N-terminal mutated forms transform RK3E
epithelial cells, wildtype and several N-terminal mutated forms of
gamma-catenin had similar transforming activity. The transforming
activity of gamma-catenin, like that of beta-catenin, was dependent on
TCF/LEF function. However, in contrast to beta-catenin, gamma-catenin
strongly activated c-myc (190080) expression and c-myc function was
crucial for gamma-catenin transformation. Kolligs et al. (2000)
suggested that APC mutations alter regulation of both beta- and
gamma-catenin, perhaps explaining why the frequency of APC mutations in
colon cancer far exceeds that of beta-catenin mutations. Elevated c-myc
expression in cancers with APC defects may be due to altered regulation
of both beta- and gamma-catenin. Furthermore, the authors stated that
their data imply beta- and gamma-catenin may have distinct roles in Wnt
signaling and cancer via differential effects on downstream target
genes.

MAPPING

Arnemann et al. (1991) established a PCR assay for the gene encoding
plakoglobin and used it to test human/mouse and human/rat somatic cell
hybrids with different contents of human chromosomes. In this way, they
were able to assign DP3 to chromosome 7. By analysis of progeny from 2
interspecific backcrosses, Guenet et al. (1995) mapped the Jup gene to
mouse chromosome 11. Thus, the human JUP gene is probably on 7p because
that is the portion of the chromosome showing homology of synteny to
mouse 11. However, mouse 11 shows much more extensive homology to human
chromosome 17 and, indeed, Aberle et al. (1995) mapped the plakoglobin
gene to 17q12-q22 by analysis of DNA from human/hamster or human/mouse
hybrid cell lines that contained only human chromosome 17 or parts
thereof. Because of evolutionary conservation, human plakoglobin cDNA
hybridized also to mouse and hamster DNA; however, the results obtained
with DNA from hybrid cells unambiguously demonstrated that the human
gene maps to chromosome 17q12-q22. The previously reported localization
to chromosome 7 was based on PCR analysis using synthetic
oligonucleotides and was not confirmed by independent work by Aberle et
al. (1995). Using a monochromosomal human-rodent somatic cell hybrid
panel, Cowley et al. (1997) likewise showed that the JUP gene is located
on chromosome 17.

Using the high-density map of polymorphic markers and genes in 17q12-q21
provided by the studies to elucidate the genetic basis of familial
breast cancer, Aberle et al. (1995) found linkage between plakoglobin
and BRCA1 (113075)-linked markers. Meiotic recombinants in the 17q
region showed that the plakoglobin gene lies between KRT10 (148080) and
D17S858, an interval that also contains the BRCA1 gene. A single
recombination event was found separating the plakoglobin gene from the
BRCA1 gene. Three plakoglobin-positive cosmid clones were found to
contain both the plakoglobin gene and the 17q21 marker locus UM8, in
close proximity (less than 40 kb).

MOLECULAR GENETICS

- Naxos Disease

McKoy et al. (2000) identified a 2-basepair deletion in homozygous state
in the plakoglobin gene in individuals affected with Naxos disease
(601214). Western blot analysis showed that the mutation causes a
frameshift and premature termination of the protein. The finding of a
deletion in plakoglobin in arrhythmogenic right ventricular
cardiomyopathy suggests that the proteins involved in cell-cell adhesion
play an important role in maintaining myocyte integrity and that when
junctions are disrupted, cell death with fatty and fibrous tissue
replacement occurs.

- Arrhythmogenic Right Ventricular Cardiomyopathy

Asimaki et al. (2007) described a dominant mutation in the gene encoding
plakoglobin in a German family with arrhythmogenic right ventricular
cardiomyopathy but no cutaneous abnormalities (ARVC12; 611528). The
mutation (173325.0002) was predicted to insert an extra serine residue
at position 39 in the N-terminus of plakoglobin. Analysis of a biopsy
sample of the right ventricle from the proband showed markedly decreased
localization of plakoglobin, desmoplakin (125647), and connexin-43
(121014) at intercalated discs in cardiac myocytes. Electron microscopy
showed smaller and fewer desmosomes in cells expressing mutant
plakoglobin. Taken together with other observations it was concluded
that the insertion mutation affected the structure and distribution of
mechanical and electrical cell junctions and could interfere with
regulatory mechanisms mediated by Wnt signaling pathways.

- Other Variation

Aberle et al. (1995) identified an arginine/histidine polymorphism due
to a substitution at nucleotide position 544 in exon 3 of the JUP gene,
leading to replacement of arginine (CGC) by histidine (CAC) at amino
acid position 142. This basepair substitution led to a loss of
recognition sites for at least 2 restriction enzymes and thereby created
an RFLP. The R142H substitution was found to represent a low-frequency
polymorphism; from a total of 240 alleles examined, the arg142-to-his
allele was found in 10 cases, giving an allele frequency of 0.042 +/-
0.013.

ANIMAL MODEL

Ruiz et al. (1996) generated mice deficient in plakoglobin by targeted
disruption. Plakoglobin mutant mouse embryos showed decreased myofiber
compliance and reduced cell-cell adhesion as a result of defects in the
number and structure of desmosomes within the myocardium. Consequently,
when myocardial cells undergo increased mechanical stress, e.g., at
embryonic day 10.5 from the onset of embryonic blood circulation, the
mice die from ventricular rupture. Plakoglobin-deficient C57BL/6 mice
that survive longer, to around birth, show an additional skin phenotype.
Epidermal desmosomes of these mice are disorganized and detached from
the cytokeratin filaments, presenting features similar to the human
blistering disease epidermolytic hyperkeratosis (Bierkamp et al., 1996).

Yin et al. (2005) found that keratinocytes cultured from Pg-null mice
exhibited weakened adhesion and increased motility. N- and C-terminally
truncated Pg deletion mutants restored adhesion, but only the
N-terminally deleted Pg suppressed single-cell migration. Both a
chemical kinase inhibitor and a dominant-negative Src tyrosine kinase
(190090) inhibited single-cell motility in Pg-null cells, whereas
constitutively active Src overcame the inhibitory effect of Pg. Yin et
al. (2005) concluded that Pg strengthens adhesion and suppresses
motility in mouse keratinocytes through both intercellular
adhesion-dependent and -independent mechanisms, the latter of which may
involve suppression of Src signaling.

*FIELD* AV
.0001
NAXOS DISEASE
JUP, 2-BP DEL, 2157TG

In patients with Naxos disease (601214), McKoy et al. (2000) identified
a 2-bp deletion at the 3-prime end of the plakoglobin gene. The deletion
of nucleotides 2157-2158 causes a frameshift and premature termination
of translation. The frameshift alters the last 5 amino acids of the
thirteenth armadillo repeat and truncates the C-terminal domain of the
putative protein by 56 residues. Western blot analysis with an
antiplakoglobin antibody confirmed the presence of mutant protein in a
cardiac biopsy sample from a patient with the disease. This mutation
destroys a Bst01 recognition site and was identified in homozygous state
in 19 affected individuals. Twenty-nine clinically unaffected family
members were heterozygous for the mutation; 20 unrelated individuals
from Naxos and 43 autosomal dominant ARVC (107970) probands were
homozygous for the normal allele.

.0002
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 12
JUP, 3-BP INS, 118GCA

In a family in which a father and 3 sons had arrhythmogenic right
ventricular cardiomyopathy (ARVD12; 611528), Asimaki et al. (2007)
identified a heterozygous 3-bp insertion (118_119GCA) in the plakoglobin
gene predicted to insert an extra serine residue at position 39 in the N
terminus of the protein (S39_K40insS).

*FIELD* RF
1. Aberle, H.; Bierkamp, C.; Torchard, D.; Serova, O.; Wagner, T.;
Natt, E.; Wirsching, J.; Heidkamper, C.; Montagna, M.; Lynch, H. T.;
Lenoir, G. M.; Scherer, G.; Feunteun, J.; Kemler, R.: The human plakoglobin
gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity
in breast and ovarian cancers. Proc. Nat. Acad. Sci. 92: 6384-6388,
1995.

2. Arnemann, J.; Spurr, N. K.; Wheeler, G. N.; Parker, A. E.; Buxton,
R. S.: Chromosomal assignment of the human genes coding for the major
proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins
DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP). Genomics 10:
640-645, 1991.

3. Asimaki, A.; Syrris, P.; Wichter, T.; Matthias, P.; Saffitz, J.
E.; McKenna, W. J.: A novel dominant mutation in plakoglobin causes
arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 81:
964-973, 2007.

4. Bierkamp, C.; Mclaughlin, K. J.; Schwarz, H.; Huber, O.; Kemler,
R.: Embryonic heart and skin defects in mice lacking plakoglobin. Dev.
Biol. 180: 780-785, 1996.

5. Cowley, C. M. E.; Simrak, D.; Spurr, N. K.; Arnemann, J.; Buxton,
R. S.: The plakophilin 1 (PKP1) and plakoglobin (JUP) genes map to
human chromosomes 1q and 17, respectively. Hum. Genet. 100: 486-488,
1997.

6. Franke, W. W.; Goldschmidt, M. D.; Zimbelmann, R.; Mueller, H.
M.; Schiller, D. L.; Cowin, P.: Molecular cloning and amino acid
sequence of human plakoglobin, the common junctional plaque protein. Proc.
Nat. Acad. Sci. 86: 4027-4031, 1989.

7. Guenet, J.-L.; Simon-Chazottes, D.; Ringwald, M.; Kemler, R.:
The genes coding for alpha and beta catenin (Catna1 and Catnb) and
plakoglobin (Jup) map to mouse chromosomes 18, 9, and 11, respectively. Mammalian
Genome 6: 363-366, 1995.

8. Knudsen, K. A.; Wheelock, M. J.: Plakoglobin, or an 83-kD homologue
distinct from beta-catenin, interacts with E-cadherin and N-cadherin. J.
Cell Biol. 118: 671-679, 1992.

9. Kolligs, F. T.; Kolligs, B.; Hajra, K. M.; Hu, G.; Tani, M.; Cho,
K. R.; Fearon, E. R.: Gamma-catenin is regulated by the APC tumor
suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes
Dev. 14: 1319-1331, 2000.

10. Mathur, M.; Goodwin, L.; Cowin, P.: Interactions of the cytoplasmic
domain of the desmosomal cadherin Dsg1 with plakoglobin. J. Biol.
Chem. 269: 14075-14080, 1994.

11. McKoy, G.; Protonotarios, N.; Crosby, A.; Tsatsopoulou, A.; Anastasakis,
A.; Coonar, A.; Norman, M.; Baboonian, C.; Jeffery, S.; McKenna, W.
J.: Identification of a deletion in plakoglobin in arrhythmogenic
right ventricular cardiomyopathy with palmoplantar keratoderma and
woolly hair (Naxos disease). Lancet 355: 2119-2124, 2000.

12. Ruiz, P.; Brinkmann, V.; Ledermann, B.; Behrend, M.; Grund, C.;
Thalhammer, C.; Vogel, F.; Birchmeier, C.; Gunthert, U.; Franke, W.
W.; Birchmeier, W.: Targeted mutation of plakoglobin in mice reveals
essential functions of desmosomes in the embryonic heart. J. Cell
Biol. 135: 215-225, 1996.

13. Yin, T.; Getsios, S.; Caldelari, R.; Kowalczyk, A. P.; Muller,
E. J.; Jones, J. C. R.; Green, K. J.: Plakoglobin suppresses keratinocyte
motility through both cell-cell adhesion-dependent and -independent
mechanisms. Proc. Nat. Acad. Sci. 102: 5420-5425, 2005.

*FIELD* CN
Victor A. McKusick - updated: 10/10/2007
Patricia A. Hartz - updated: 6/30/2005
Ada Hamosh - updated: 8/4/2000
Patti M. Sherman - updated: 7/13/2000
Victor A. McKusick - updated: 8/27/1997

*FIELD* CD
Victor A. McKusick: 7/11/1990

*FIELD* ED
ckniffin: 02/05/2008
alopez: 10/12/2007
terry: 10/10/2007
wwang: 8/4/2005
wwang: 7/21/2005
terry: 6/30/2005
carol: 8/4/2000
mcapotos: 8/3/2000
mcapotos: 7/27/2000
mcapotos: 7/21/2000
psherman: 7/13/2000
psherman: 11/2/1999
mark: 9/3/1997
terry: 8/27/1997
alopez: 7/30/1997
jenny: 7/9/1997
terry: 6/18/1996
terry: 6/3/1996
mark: 8/1/1995
supermim: 3/16/1992
carol: 6/20/1991
carol: 7/11/1990

MIM 601214
*RECORD*
*FIELD* NO
601214
*FIELD* TI
#601214 NAXOS DISEASE
;;MAL DE NAXOS;;
KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY;;
read moreWOOLLY HAIR, PALMOPLANTAR KERATODERMA, AND CARDIAC ABNORMALITIES;;
PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY
AND WOOLLY HAIR
*FIELD* TX
A number sign (#) is used with this entry because of evidence that Naxos
disease can be caused by homozygous mutation in the plakoglobin gene
(JUP; 173325) on chromosome 17q21.

CLINICAL FEATURES

Naxos disease is an autosomal recessive disorder that combines
palmoplantar keratoderma and other ectodermal features with cardiac
disorders suggesting arrhythmogenic right ventricular
dysplasia/cardiomyopathy (see ARVD/C; 107970). It was first reported in
families on the Greek island of Naxos by Protonotarios et al. (1986). At
that time the authors described 4 families and 9 cases. Seven of the 9
affected persons showed signs and symptoms of heart disease, including
cardiomegaly, EKG abnormalities, episodes of ventricular tachycardia,
and, in 1 patient, sudden death. All patients had echocardiographic
evidence of enlargement of the right ventricle and a right ventricular
band; in 3, the left ventricle was also affected. Protonotarios et al.
(1986) pictured the scalp hair, which was described as dense, rough, and
bristly, resembling steel wire. One patient was thought to have Ebstein
anomaly (224700) with additional right ventricular myocardial dysplasia.

Barker et al. (1988) emphasized the association of curly hair and the
cardiac abnormality with palmoplantar keratoderma. The association
between dilated cardiomyopathy with associated cardiac arrhythmias and
ectodermal dysplasia was reported in 3 children by Hammill et al.
(1988).

Tosti et al. (1994) described 2 members of a family who had curly hair
with diffuse palmoplantar keratoderma of the Unna-Thost type (144200)
associated with asymptomatic right ventricular dysfunction. A skin
biopsy specimen from the plantar lesions showed only compact
hyperkeratosis, hypergranulosis, and acanthosis.

MOLECULAR GENETICS

McKoy et al. (2000) identified homozygosity for a 2-basepair deletion in
the plakoglobin gene (173325.0001) in 19 affected individuals with Naxos
disease. Twenty-nine clinically unaffected family members were
heterozygous for the mutation; 20 unrelated individuals from Naxos and
43 autosomal dominant ARVC probands were homozygous for the normal
allele.

HETEROGENEITY

Schonberger and Seidman (2001) reviewed the genetics of dilated
cardiomyopathy. They listed 26 different forms which had been mapped to
different chromosomal locations. The molecular defect had been defined
in 12 of these. They pointed out that the overwhelming majority of these
forms (22) are autosomal dominant. There are 2 X-linked dilated
cardiomyopathies and 2 autosomal recessive: Naxos disease and a
clinically related disorder of dilated cardiomyopathy with woolly hair
and keratoderma (605676), due to a defect in desmoplakin (125647), which
maps to 6p24.

Djabali et al. (2002) reported the clinical findings in 2 Arab families
with Naxos disease originating from villages near Jerusalem. They
excluded both plakoglobin and desmoplakin as candidate genes in these
families. In addition, they excluded genes encoding keratin type I (see
148020) and type II (see 148041) on chromosomes 17 and 12, respectively;
desmoyokin (103390) on 11q13.1; the desmocollin/desmoglein cluster on
18q12.1 (see 125643); plakophilin-1 (601975) on 1q32; plakophilin-2
(602861) on 12p13; and plakophilin-4 (604276) on 2q23-q31. These
findings emphasized the genetic heterogeneity of Naxos disease.

*FIELD* RF
1. Barker, J. N. W. N.; Protonatorios, N.; Tsatopoulou, A.; MacDonald,
D. M.: Palmoplantar keratoderma, curly hair and endomyocardial fibrodysplasia:
a new syndrome. (Abstract) Brit. J. Derm. 119 (suppl. 33): 13-14,
1988.

2. Djabali, K.; Martinez-Mir, A.; Horev, L.; Klapholz, L.; Glaser,
B.; Christiano, A. M.; Zlotogorski, A.: Evidence for extensive locus
heterogeneity in Naxos disease. J. Invest. Derm. 118: 557-560, 2002.

3. Hammill, W. W.; Fyfe, D. A.; Gillette, P. C.; Taylor, A.; Dobson,
R. L.; Thompson, R. P.: Cardiomyopathy with arrhythmias and ectodermal
dysplasia: a previously unreported association. Am. Heart J. 115:
373-377, 1988.

4. McKoy, G.; Protonotarios, N.; Crosby, A.; Tsatsopoulou, A.; Anastasakis,
A.; Coonar, A.; Norman, M.; Baboonian, C.; Jeffery, S.; McKenna, W.
J.: Identification of a deletion in plakoglobin in arrhythmogenic
right ventricular cardiomyopathy with palmoplantar keratoderma and
woolly hair (Naxos disease). Lancet 355: 2119-2124, 2000.

5. Protonotarios, N.; Tsatsopoulou, A.; Patsourakos, P.; Alexopoulos,
D.; Gezerlis, P.; Simitsis, S.; Scampardonis, G.: Cardiac abnormalities
in familial palmoplantar keratosis. Brit. Heart J. 56: 321-326,
1986.

6. Schonberger, J.; Seidman, C. E.: Many roads lead to a broken heart:
the genetics of dilated cardiomyopathy. Am. J. Hum. Genet. 69: 249-260,
2001.

7. Tosti, A.; Misciali, C.; Piraccini, B. M.; Fanti, P. A.; Barbareschi,
M.; Ferretti, R. M.: Woolly hair, palmoplantar keratoderma, and cardiac
abnormalities: report of a family. Arch. Derm. 130: 522-524, 1994.

*FIELD* CS
INHERITANCE:
Autosomal recessive

CARDIOVASCULAR:
[Heart];
Cardiomegaly;
Dilated cardiomyopathy;
Arrhythmogenic right ventricular dysplasia;
Episodes of ventricular tachycardia;
EKG abnormalities;
Sudden death

SKIN, NAILS, HAIR:
[Skin];
Palmoplantar keratoderma;
[Hair];
Woolly hair;
Curly hair;
Dense, rough, and bristly hair

MOLECULAR BASIS:
Caused by mutation in the plakoglobin gene (JUP, 173325.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 1/9/2003

*FIELD* CD
John F. Jackson: 10/8/1998

*FIELD* ED
joanna: 03/14/2005
ckniffin: 1/9/2003
alopez: 2/23/2001

*FIELD* CN
Gary A. Bellus - updated: 3/5/2003
Cassandra L. Kniffin - reorganized: 1/9/2003
Victor A. McKusick - updated: 8/30/2001
Ada Hamosh - updated: 8/4/2000
Victor A. McKusick - updated: 2/19/1999

*FIELD* CD
Victor A. McKusick: 4/19/1996

*FIELD* ED
carol: 12/14/2012
mgross: 4/7/2011
terry: 8/20/2010
terry: 2/19/2009
alopez: 3/5/2003
carol: 1/9/2003
ckniffin: 1/9/2003
cwells: 9/20/2001
cwells: 9/18/2001
terry: 8/30/2001
alopez: 2/23/2001
terry: 8/7/2000
carol: 8/4/2000
carol: 11/11/1999
terry: 11/11/1999
carol: 2/22/1999
terry: 2/19/1999
alopez: 7/10/1997
jamie: 12/18/1996
mark: 6/7/1996
terry: 6/5/1996
mark: 4/19/1996

MIM 611528
*RECORD*
*FIELD* NO
611528
*FIELD* TI
#611528 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 12; ARVD12
;;ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 12; ARVC12
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
arrhythmogenic right ventricular dysplasia-12 (ARVD12) is caused by
heterozygous mutation in the gene encoding junction plakoglobin (JUP;
173325) on chromosome 17q21.

For a general phenotypic description and a discussion of genetic
heterogeneity of this disorder, see ARVD1 (107970).

CLINICAL FEATURES

Asimaki et al. (2007) described a German family in which the father and
3 sons had arrhythmogenic right ventricular cardiomyopathy. The proband
experienced syncope at age 39 years. After a documented episode of
sustained ventricular tachycardia he was admitted to the hospital for
further diagnostic evaluation and management. Electrocardiography
demonstrated QRS prolongation, T wave inversion, and late potentials in
right precordial leads. Angiography showed moderate global right
ventricular dilatation and regional wall-motion abnormalities without
left ventricular involvement. Sustained monomorphic ventricular
tachycardia of left bundle branch block morphology was induced at
electrophysiologic study. Biopsy of an endomyocardial sample showed
extensive fibrofatty replacement of right ventricular muscle and patchy
mononuclear inflammatory infiltrate. These phenotypes led to the
diagnosis of arrhythmogenic right ventricular cardiomyopathy. Skin and
hair appeared grossly normal. The proband's brothers received diagnoses
of arrhythmogenic right ventricular cardiomyopathy after cardiac
evaluation on the basis of 12-lead and 24-hour electrocardiography and
echocardiographic abnormalities. The father had died at age 70 of heart
failure and was presumed to have had the disorder.

MOLECULAR GENETICS

In a German family with arrhythmogenic right ventricular cardiomyopathy
in a father and 3 sons, Asimaki et al. (2007) identified a novel
mutation in the plakoglobin gene, predicted to result in the insertion
of an extra serine residue after ser39 in the N terminus of the protein
(173325.0002). There were no dermatologic manifestations such as those
seen in Naxos disease (601214), a recessive disorder also due to
mutation in the plakoglobin gene associated with abnormalities of hair
and skin.

*FIELD* RF
1. Asimaki, A.; Syrris, P.; Wichter, T.; Matthias, P.; Saffitz, J.
E.; McKenna, W. J.: A novel dominant mutation in plakoglobin causes
arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 81:
964-973, 2007.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, right ventricular;
Fibrofatty replacement of right ventricular myocardium;
Ventricular arrhythmia (sustained VT);
Syncope

SKIN, NAILS, HAIR:
[Skin];
Normal skin (no palmoplantar keratoderma);
[Hair];
Normal hair (no woolly hair)

MISCELLANEOUS:
Genetic heterogeneity;
Allelic to Naxos disease (601214)

MOLECULAR BASIS:
Caused by mutation in the junction plakoglobin gene (JUP, 173325.0002).

*FIELD* CD
Kelly A. Przylepa: 10/12/2007

*FIELD* ED
joanna: 04/27/2009
terry: 2/20/2009
joanna: 3/6/2008
alopez: 10/12/2007

*FIELD* CD
Victor A. McKusick: 10/12/2007

*FIELD* ED
carol: 01/24/2014
mcolton: 1/24/2014
alopez: 10/12/2007