RBCC Red Blood Cell Collection

DSP [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Desmoplakin; DP (250/210 kDa paraneoplastic pemphigus antigen)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P15924
ID DESP_HUMAN Reviewed; 2871 AA.
AC P15924; B2RTT2; O75993; Q14189; Q9UHN4;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-OCT-2006, sequence version 3.
DT 22-JAN-2014, entry version 175.
DE RecName: Full=Desmoplakin;
DE Short=DP;
DE AltName: Full=250/210 kDa paraneoplastic pemphigus antigen;
GN Name=DSP;
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 DPI).
RC TISSUE=Foreskin;
RX PubMed=1731325; DOI=10.1073/pnas.89.2.544;
RA Virata M.L.A., Wagner R.M., Parry D.A.D., Green K.J.;
RT "Molecular structure of the human desmoplakin I and II amino
RT terminus.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:544-548(1992).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM DPII).
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1120-2871 (ISOFORM DPI).
RC TISSUE=Foreskin;
RX PubMed=1689290;
RA Green K.J., Parry D.A.D., Steinert P.M., Virata M.L.A., Wagner R.M.,
RA Angst B.D., Nilles L.A.;
RT "Structure of the human desmoplakins. Implications for function in the
RT desmosomal plaque.";
RL J. Biol. Chem. 265:2603-2612(1990).
RN [5]
RP ERRATUM.
RX PubMed=2391353;
RA Green K.J., Parry D.A.D., Steinert P.M., Virata M.L.A., Wagner R.M.,
RA Angst B.D., Nilles L.A.;
RL J. Biol. Chem. 265:11406-11407(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2854-2871.
RC TISSUE=Skin;
RX PubMed=10594734; DOI=10.1046/j.1523-1747.1999.00783.x;
RA Whittock N.V., Ashton G.H., Dopping-Hepenstal P.J., Gratian M.J.,
RA Keane F.M., Eady R.A.J., McGrath J.A.;
RT "Striate palmoplantar keratoderma resulting from desmoplakin
RT haploinsufficiency.";
RL J. Invest. Dermatol. 113:940-946(1999).
RN [7]
RP CHARACTERIZATION.
RX PubMed=9348293; DOI=10.1083/jcb.139.3.773;
RA Kowalczyk A.P., Bornslaeger E.A., Borgwardt J.E., Palka H.L.,
RA Dhaliwal A.S., Corcoran C.M., Denning M.F., Green K.J.;
RT "The amino-terminal domain of desmoplakin binds to plakoglobin and
RT clusters desmosomal cadherin-plakoglobin complexes.";
RL J. Cell Biol. 139:773-784(1997).
RN [8]
RP LIPIDATION.
RX PubMed=9651377; DOI=10.1074/jbc.273.28.17763;
RA Marekov L.N., Steinert P.M.;
RT "Ceramides are bound to structural proteins of the human foreskin
RT epidermal cornified cell envelope.";
RL J. Biol. Chem. 273:17763-17770(1998).
RN [9]
RP INVOLVEMENT IN SPPK2.
RX PubMed=9887343; DOI=10.1093/hmg/8.1.143;
RA Armstrong D.K., McKenna K.E., Purkis P.E., Green K.J., Eady R.A.J.,
RA Leigh I.M., Hughes A.E.;
RT "Haploinsufficiency of desmoplakin causes a striate subtype of
RT palmoplantar keratoderma.";
RL Hum. Mol. Genet. 8:143-148(1999).
RN [10]
RP ERRATUM.
RA Armstrong D.K., McKenna K.E., Purkis P.E., Green K.J., Eady R.A.J.,
RA Leigh I.M., Hughes A.E.;
RL Hum. Mol. Genet. 8:943-943(1999).
RN [11]
RP INVOLVEMENT IN DCWHK.
RX PubMed=11063735; DOI=10.1093/hmg/9.18.2761;
RA Norgett E.E., Hatsell S.J., Carvajal-Huerta L., Cabezas J.-C.R.,
RA Common J., Purkis P.E., Whittock N.V., Leigh I.M., Stevens H.P.,
RA Kelsell D.P.;
RT "Recessive mutation in desmoplakin disrupts desmoplakin-intermediate
RT filament interactions and causes dilated cardiomyopathy, woolly hair
RT and keratoderma.";
RL Hum. Mol. Genet. 9:2761-2766(2000).
RN [12]
RP INTERACTION WITH COL17A1.
RX PubMed=12482924; DOI=10.1242/jcs.00241;
RA Koster J., Geerts D., Favre B., Borradori L., Sonnenberg A.;
RT "Analysis of the interactions between BP180, BP230, plectin and the
RT integrin alpha6beta4 important for hemidesmosome assembly.";
RL J. Cell Sci. 116:387-399(2003).
RN [13]
RP ASSOCIATION WITH KERATIN FILAMENTS, MUTAGENESIS OF SER-2849, AND
RP SUBCELLULAR LOCATION.
RX PubMed=12802069; DOI=10.1091/mbc.E02-08-0548;
RA Fontao L., Favre B., Riou S., Geerts D., Jaunin F., Saurat J.H.,
RA Green K.J., Sonnenberg A., Borradori L.;
RT "Interaction of the bullous pemphigoid antigen 1 (BP230) and
RT desmoplakin with intermediate filaments is mediated by distinct
RT sequences within their COOH terminus.";
RL Mol. Biol. Cell 14:1978-1992(2003).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2825, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-165; SER-166; SER-176;
RP SER-2024; SER-2209; SER-2815; SER-2821; SER-2825; SER-2849; THR-2853
RP AND SER-2868, AND MASS SPECTROMETRY.
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2024; SER-2207;
RP SER-2209; SER-2815 AND SER-2825, AND MASS 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 [21]
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 [22]
RP INTERACTION WITH DSC2, AND VARIANT VAL-1833.
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 [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22; SER-2209; SER-2820
RP AND SER-2825, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [24]
RP INTERACTION WITH PKP2.
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 [25]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 2209-2456, X-RAY
RP CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 2609-2822, AND DOMAIN PLAKIN
RP REPEATS.
RX PubMed=12101406; DOI=10.1038/nsb818;
RA Choi H.J., Park-Snyder S., Pascoe L.T., Green K.J., Weis W.I.;
RT "Structures of two intermediate filament-binding fragments of
RT desmoplakin reveal a unique repeat motif structure.";
RL Nat. Struct. Biol. 9:612-620(2002).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) OF 178-627, DOMAIN SPECTRIN
RP REPEATS, AND DOMAIN SH3.
RX PubMed=21536047; DOI=10.1016/j.jmb.2011.04.046;
RA Choi H.J., Weis W.I.;
RT "Crystal structure of a rigid four-spectrin-repeat fragment of the
RT human desmoplakin plakin domain.";
RL J. Mol. Biol. 409:800-812(2011).
RN [27]
RP VARIANT ARVD8 ARG-299.
RX PubMed=12373648; DOI=10.1086/344208;
RA Rampazzo A., Nava A., Malacrida S., Beffagna G., Bauce B., Rossi V.,
RA Zimbello R., Simionati B., Basso C., Thiene G., Towbin J.A.,
RA Danieli G.A.;
RT "Mutation in human desmoplakin domain binding to plakoglobin causes a
RT dominant form of arrhythmogenic right ventricular cardiomyopathy.";
RL Am. J. Hum. Genet. 71:1200-1206(2002).
RN [28]
RP VARIANTS SFWHS LYS-287 AND CYS-2366.
RX PubMed=11841538; DOI=10.1046/j.0022-202x.2001.01664.x;
RA Whittock N.V., Wan H., Morley S.M., Garzon M.C., Kristal L., Hyde P.,
RA McLean W.H.I., Pulkkinen L., Uitto J., Christiano A.M., Eady R.A.J.,
RA McGrath J.A.;
RT "Compound heterozygosity for non-sense and mis-sense mutations in
RT desmoplakin underlies skin fragility/woolly hair syndrome.";
RL J. Invest. Dermatol. 118:232-238(2002).
RN [29]
RP VARIANT ARRHYTHMOGENIC CARDIOMYOPATHY ARG-2375.
RX PubMed=12875771; DOI=10.1016/S0735-1097(03)00628-4;
RA Alcalai R., Metzger S., Rosenheck S., Meiner V., Chajek-Shaul T.;
RT "A recessive mutation in desmoplakin causes arrhythmogenic right
RT ventricular dysplasia, skin disorder, and woolly hair.";
RL J. Am. Coll. Cardiol. 42:319-327(2003).
RN [30]
RP INVOLVEMENT IN LETHAL ACANTHOLYTIC EPIDERMOLYSIS BULLOSA.
RX PubMed=16175511; DOI=10.1086/496901;
RA Jonkman M.F., Pasmooij A.M.G., Pasmans S.G.M.A., van den Berg M.P.,
RA Ter Horst H.J., Timmer A., Pas H.H.;
RT "Loss of desmoplakin tail causes lethal acantholytic epidermolysis
RT bullosa.";
RL Am. J. Hum. Genet. 77:653-660(2005).
RN [31]
RP VARIANTS ARVD8 ARG-299; LYS-1255 AND ILE-1775.
RX PubMed=15941723; DOI=10.1093/eurheartj/ehi341;
RA Bauce B., Basso C., Rampazzo A., Beffagna G., Daliento L., Frigo G.,
RA Malacrida S., Settimo L., Danieli G., Thiene G., Nava A.;
RT "Clinical profile of four families with arrhythmogenic right
RT ventricular cardiomyopathy caused by dominant desmoplakin mutations.";
RL Eur. Heart J. 26:1666-1675(2005).
RN [32]
RP VARIANTS ARVD8 ARG-299; LYS-1255 AND ILE-1775, AND VARIANTS PHE-305;
RP VAL-1505; CYS-1512; LYS-1526; CYS-1537 AND GLN-1738.
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 [33]
RP VARIANTS PHE-305; CYS-1512; LYS-1526; CYS-1537; CYS-1537; GLN-1738 AND
RP VAL-1833.
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: Major high molecular weight protein of desmosomes.
CC Involved in the organization of the desmosomal cadherin-
CC plakoglobin complexes into discrete plasma membrane domains and in
CC the anchoring of intermediate filaments to the desmosomes.
CC -!- SUBUNIT: Homodimer. Interacts with COL17A1 (via cytoplasmic
CC region). Associates (via C-terminal) with KRT5-KRT14 (via rod
CC region), KRT8-KRT18 and VIM intermediate filaments. Interacts with
CC DSC2. Interacts with PKP2.
CC -!- SUBCELLULAR LOCATION: Cell junction, desmosome. Cytoplasm,
CC cytoskeleton. Note=Innermost portion of the desmosomal plaque.
CC Colocalizes with epidermal KRT5-KRT14 and simple KRT8-KRT18
CC keratins and VIM intermediate filaments network.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=DPI; Synonyms=DP1;
CC IsoId=P15924-1; Sequence=Displayed;
CC Name=DPII; Synonyms=DP2;
CC IsoId=P15924-2; Sequence=VSP_005070;
CC -!- TISSUE SPECIFICITY: Isoform DPI is apparently an obligate
CC constituent of all desmosomes. Isoform DPII resides predominantly
CC in tissues and cells of stratified origin.
CC -!- DOMAIN: Its association with epidermal and simple keratins is
CC dependent on the tertiary structure induced by heterodimerization
CC of these intermediate filaments proteins and most likely involves
CC recognition sites located in the rod domain of these keratins.
CC -!- DOMAIN: The N-terminal region is required for localization to the
CC desmosomal plaque and interacts with the N-terminal region of
CC plakophilin 1.
CC -!- DOMAIN: The three tandem plakin repeat regions in the C-terminus
CC mediate binding to intermediate filaments.
CC -!- PTM: Ser-2849 is probably phosphorylated by a cAMP-dependent
CC protein kinase. Phosphorylation on Ser-2849 probably affects its
CC association with epidermal, simple cytokeratins and VIM
CC intermediate filaments.
CC -!- PTM: Substrate of transglutaminase. Some glutamines and lysines
CC are cross-linked to other desmoplakin molecules, to other proteins
CC such as keratin, envoplakin, periplakin and involucrin, and to
CC lipids like omega-hydroxyceramide.
CC -!- DISEASE: Keratoderma, palmoplantar, striate 2 (SPPK2)
CC [MIM:612908]: A dermatological disorder characterized by
CC thickening of the skin on the palms (linear pattern) and the soles
CC (island-like pattern) and flexor aspect of the fingers.
CC Abnormalities of the nails, the teeth and the hair are rarely
CC present. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated, with woolly hair and keratoderma
CC (DCWHK) [MIM:605676]: An autosomal recessive cardiocutaneous
CC syndrome characterized by a generalized striate keratoderma
CC particularly affecting the palmoplantar epidermis, woolly hair,
CC and dilated left ventricular cardiomyopathy. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Arrhythmogenic right ventricular dysplasia, familial, 8
CC (ARVD8) [MIM:607450]: 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 -!- DISEASE: Skin fragility-woolly hair syndrome (SFWHS) [MIM:607655]:
CC An autosomal recessive genodermatosis characterized by skin
CC fragility with blistering, focal and diffuse palmoplantar
CC keratoderma, hyperkeratotic plaques on the trunk and limbs, and
CC woolly hair with varying degrees of alopecia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Epidermolysis bullosa, lethal acantholytic (EBLA)
CC [MIM:609638]: A form of epidermolysis bullosa characterized by
CC severe fragility of skin and mucous membranes. The phenotype is
CC lethal in the neonatal period because of immense transcutaneous
CC fluid loss. Typical features include universal alopecia, neonatal
CC teeth, and nail loss. Histopathology of the skin shows suprabasal
CC clefting and acantholysis throughout the spinous layer, mimicking
CC pemphigus. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the plakin or cytolinker family.
CC -!- SIMILARITY: Contains 17 plectin repeats.
CC -!- SIMILARITY: Contains 1 SH3 domain.
CC -!- SIMILARITY: Contains 6 spectrin repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/DSP";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Desmoplakin entry;
CC URL="http://en.wikipedia.org/wiki/Desmoplakin";
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DR EMBL; M77830; AAA85135.1; -; mRNA.
DR EMBL; AL031058; CAA19927.1; -; Genomic_DNA.
DR EMBL; BC140802; AAI40803.1; -; mRNA.
DR EMBL; J05211; AAA35766.1; -; mRNA.
DR EMBL; AF139065; AAF19785.1; -; mRNA.
DR PIR; A38194; A38194.
DR RefSeq; NP_001008844.1; NM_001008844.1.
DR RefSeq; NP_004406.2; NM_004415.2.
DR UniGene; Hs.519873; -.
DR PDB; 1LM5; X-ray; 1.80 A; A/B=2609-2822.
DR PDB; 1LM7; X-ray; 3.00 A; A/B=2209-2456.
DR PDB; 3R6N; X-ray; 2.95 A; A/B=178-627.
DR PDBsum; 1LM5; -.
DR PDBsum; 1LM7; -.
DR PDBsum; 3R6N; -.
DR ProteinModelPortal; P15924; -.
DR SMR; P15924; 178-627, 2209-2448, 2613-2808.
DR DIP; DIP-109N; -.
DR IntAct; P15924; 20.
DR MINT; MINT-1157663; -.
DR STRING; 9606.ENSP00000369129; -.
DR PhosphoSite; P15924; -.
DR DMDM; 115502381; -.
DR PaxDb; P15924; -.
DR PeptideAtlas; P15924; -.
DR PRIDE; P15924; -.
DR Ensembl; ENST00000379802; ENSP00000369129; ENSG00000096696.
DR Ensembl; ENST00000418664; ENSP00000396591; ENSG00000096696.
DR GeneID; 1832; -.
DR KEGG; hsa:1832; -.
DR UCSC; uc003mxp.1; human.
DR CTD; 1832; -.
DR GeneCards; GC06P007541; -.
DR HGNC; HGNC:3052; DSP.
DR HPA; CAB037324; -.
DR MIM; 125647; gene.
DR MIM; 605676; phenotype.
DR MIM; 607450; phenotype.
DR MIM; 607655; phenotype.
DR MIM; 609638; phenotype.
DR MIM; 612908; phenotype.
DR neXtProt; NX_P15924; -.
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; 2032; Idiopathic pulmonary fibrosis.
DR Orphanet; 50942; Keratosis palmoplantaris striata.
DR Orphanet; 158687; Lethal acantholytic epidermolysis bullosa.
DR Orphanet; 293165; Skin fragility-woolly hair-palmoplantar keratoderma syndrome.
DR Orphanet; 65282; Woolly hair-palmoplantar keratoderma-dilated cardiomyopathy syndrome.
DR PharmGKB; PA27505; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000112198; -.
DR HOVERGEN; HBG081434; -.
DR InParanoid; P15924; -.
DR KO; K10381; -.
DR OMA; KRSMSFQ; -.
DR OrthoDB; EOG7TQTZV; -.
DR PhylomeDB; P15924; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; DSP; human.
DR EvolutionaryTrace; P15924; -.
DR GeneWiki; Desmoplakin; -.
DR GenomeRNAi; 1832; -.
DR NextBio; 7481; -.
DR PRO; PR:P15924; -.
DR ArrayExpress; P15924; -.
DR Bgee; P15924; -.
DR CleanEx; HS_DSP; -.
DR Genevestigator; P15924; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl.
DR GO; GO:0001533; C:cornified envelope; IDA:UniProtKB.
DR GO; GO:0030057; C:desmosome; IEA:UniProtKB-SubCell.
DR GO; GO:0014704; C:intercalated disc; IDA:BHF-UCL.
DR GO; GO:0005882; C:intermediate filament; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR GO; GO:0030674; F:protein binding, bridging; IDA:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0034332; P:adherens junction organization; IEA:Ensembl.
DR GO; GO:0086069; P:bundle of His cell to Purkinje myocyte communication; IMP:BHF-UCL.
DR GO; GO:0016337; P:cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0002934; P:desmosome organization; ISS:BHF-UCL.
DR GO; GO:0045109; P:intermediate filament organization; ISS:BHF-UCL.
DR GO; GO:0030216; P:keratinocyte differentiation; IDA:UniProtKB.
DR GO; GO:0018149; P:peptide cross-linking; IDA:UniProtKB.
DR GO; GO:0071896; P:protein localization to adherens junction; ISS: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:0003223; P:ventricular compact myocardium morphogenesis; ISS:BHF-UCL.
DR InterPro; IPR028462; Desmoplakin.
DR InterPro; IPR001101; Plectin_repeat.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR PANTHER; PTHR11915:SF196; PTHR11915:SF196; 1.
DR Pfam; PF00681; Plectin; 8.
DR SMART; SM00250; PLEC; 18.
DR SMART; SM00150; SPEC; 3.
DR PROSITE; PS50002; SH3; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cardiomyopathy; Cell junction;
KW Coiled coil; Complete proteome; Cytoplasm; Cytoskeleton;
KW Disease mutation; Epidermolysis bullosa; Lipoprotein;
KW Palmoplantar keratoderma; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat.
FT CHAIN 1 2871 Desmoplakin.
FT /FTId=PRO_0000078144.
FT REPEAT 178 271 Spectrin 1.
FT REPEAT 272 375 Spectrin 2.
FT REPEAT 376 446 Spectrin 3a.
FT DOMAIN 447 515 SH3.
FT REPEAT 516 545 Spectrin 3b.
FT REPEAT 546 627 Spectrin 4.
FT REPEAT 654 769 Spectrin 5.
FT REPEAT 770 883 Spectrin 6.
FT REPEAT 2009 2045 Plectin 1.
FT REPEAT 2046 2083 Plectin 2.
FT REPEAT 2084 2121 Plectin 3.
FT REPEAT 2122 2159 Plectin 4.
FT REPEAT 2163 2197 Plectin 5.
FT REPEAT 2198 2233 Plectin 6.
FT REPEAT 2251 2288 Plectin 7.
FT REPEAT 2289 2326 Plectin 8.
FT REPEAT 2327 2364 Plectin 9.
FT REPEAT 2365 2402 Plectin 10.
FT REPEAT 2406 2440 Plectin 11.
FT REPEAT 2456 2493 Plectin 12.
FT REPEAT 2507 2544 Plectin 13.
FT REPEAT 2610 2647 Plectin 14.
FT REPEAT 2648 2685 Plectin 15.
FT REPEAT 2724 2761 Plectin 16.
FT REPEAT 2762 2799 Plectin 17.
FT REGION 1 1056 Globular 1.
FT REGION 1 584 Interacts with plakophilin 1 and junction
FT plakoglobin.
FT REGION 1057 1945 Central fibrous rod domain.
FT REGION 1946 2871 Globular 2.
FT REGION 1960 2208 4.5 X 38 AA tandem repeats (Domain A).
FT REGION 2244 2446 4.5 X 38 AA tandem repeats (Domain B).
FT REGION 2609 2822 4.5 X 38 AA tandem repeats (Domain C).
FT REGION 2824 2847 6 X 4 AA tandem repeats of G-S-R-[SR].
FT COILED 1018 1945 Potential.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 165 165 Phosphoserine.
FT MOD_RES 166 166 Phosphoserine.
FT MOD_RES 176 176 Phosphoserine.
FT MOD_RES 2024 2024 Phosphoserine.
FT MOD_RES 2207 2207 Phosphoserine.
FT MOD_RES 2209 2209 Phosphoserine.
FT MOD_RES 2815 2815 Phosphoserine.
FT MOD_RES 2820 2820 Phosphoserine.
FT MOD_RES 2821 2821 Phosphoserine.
FT MOD_RES 2825 2825 Phosphoserine.
FT MOD_RES 2849 2849 Phosphoserine.
FT MOD_RES 2853 2853 Phosphothreonine.
FT MOD_RES 2868 2868 Phosphoserine.
FT LIPID 2480 2480 Omega-hydroxyceramide glutamate ester
FT (Potential).
FT VAR_SEQ 1195 1793 Missing (in isoform DPII).
FT /FTId=VSP_005070.
FT VARIANT 287 287 N -> K (in SFWHS).
FT /FTId=VAR_015569.
FT VARIANT 299 299 S -> R (in ARVD8; dbSNP:rs121912992).
FT /FTId=VAR_015402.
FT VARIANT 305 305 I -> F (in dbSNP:rs17604693).
FT /FTId=VAR_033862.
FT VARIANT 445 445 I -> V (in ARVD8).
FT /FTId=VAR_065693.
FT VARIANT 1255 1255 R -> K (in ARVD8).
FT /FTId=VAR_023814.
FT VARIANT 1505 1505 A -> V.
FT /FTId=VAR_065694.
FT VARIANT 1512 1512 Y -> C (in dbSNP:rs2076299).
FT /FTId=VAR_020468.
FT VARIANT 1526 1526 N -> K (in dbSNP:rs28763966).
FT /FTId=VAR_065695.
FT VARIANT 1537 1537 R -> C (in dbSNP:rs28763967).
FT /FTId=VAR_065696.
FT VARIANT 1738 1738 R -> Q (in dbSNP:rs6929069).
FT /FTId=VAR_023815.
FT VARIANT 1775 1775 R -> I (in ARVD8; dbSNP:rs34738426).
FT /FTId=VAR_023816.
FT VARIANT 1833 1833 E -> V (in dbSNP:rs78652302).
FT /FTId=VAR_065697.
FT VARIANT 2366 2366 R -> C (in SFWHS; dbSNP:rs28931610).
FT /FTId=VAR_015570.
FT VARIANT 2375 2375 G -> R (in a case of recessive
FT arrhythmogenic right ventricular
FT cardiomyopathy with skin abnormalities
FT and woolly hair).
FT /FTId=VAR_018158.
FT MUTAGEN 2849 2849 S->G: Increases association with KRT5-
FT KRT14, KRT8-KRT18 or VIM intermediate
FT filaments.
FT CONFLICT 905 905 A -> R (in Ref. 1; AAA85135).
FT CONFLICT 1120 1120 D -> R (in Ref. 4; AAA35766).
FT CONFLICT 2687 2688 RL -> SV (in Ref. 1; AAA85135 and 4;
FT AAA35766).
FT HELIX 182 201
FT HELIX 211 241
FT HELIX 245 294
FT HELIX 307 338
FT HELIX 344 402
FT HELIX 411 442
FT HELIX 449 451
FT STRAND 462 467
FT STRAND 469 471
FT STRAND 474 476
FT STRAND 481 486
FT STRAND 488 496
FT STRAND 498 500
FT STRAND 503 506
FT HELIX 507 509
FT HELIX 517 561
FT HELIX 565 568
FT TURN 573 575
FT HELIX 576 594
FT HELIX 602 624
FT STRAND 2213 2217
FT HELIX 2219 2224
FT HELIX 2230 2237
FT HELIX 2246 2249
FT HELIX 2251 2254
FT STRAND 2260 2265
FT TURN 2266 2269
FT STRAND 2270 2273
FT HELIX 2274 2278
FT STRAND 2279 2283
FT HELIX 2285 2296
FT STRAND 2301 2303
FT TURN 2304 2307
FT STRAND 2308 2310
FT HELIX 2312 2317
FT TURN 2323 2333
FT HELIX 2334 2337
FT TURN 2342 2344
FT HELIX 2350 2354
FT TURN 2355 2357
FT HELIX 2361 2372
FT TURN 2373 2375
FT STRAND 2376 2378
FT TURN 2380 2382
FT STRAND 2384 2386
FT HELIX 2388 2393
FT HELIX 2399 2406
FT STRAND 2414 2417
FT TURN 2418 2421
FT STRAND 2422 2424
FT HELIX 2426 2431
FT TURN 2437 2439
FT STRAND 2442 2446
FT STRAND 2619 2624
FT TURN 2625 2628
FT STRAND 2629 2631
FT HELIX 2633 2638
FT HELIX 2644 2655
FT TURN 2656 2658
FT STRAND 2659 2661
FT TURN 2663 2665
FT HELIX 2671 2676
FT HELIX 2682 2696
FT HELIX 2709 2714
FT HELIX 2720 2732
FT HELIX 2739 2741
FT HELIX 2747 2752
FT HELIX 2758 2765
FT HELIX 2767 2769
FT TURN 2777 2779
FT HELIX 2785 2791
FT TURN 2796 2798
FT STRAND 2801 2805
SQ SEQUENCE 2871 AA; 331774 MW; 5770CC6B4F9F9F7B CRC64;
MSCNGGSHPR INTLGRMIRA ESGPDLRYEV TSGGGGTSRM YYSRRGVITD QNSDGYCQTG
TMSRHQNQNT IQELLQNCSD CLMRAELIVQ PELKYGDGIQ LTRSRELDEC FAQANDQMEI
LDSLIREMRQ MGQPCDAYQK RLLQLQEQMR ALYKAISVPR VRRASSKGGG GYTCQSGSGW
DEFTKHVTSE CLGWMRQQRA EMDMVAWGVD LASVEQHINS HRGIHNSIGD YRWQLDKIKA
DLREKSAIYQ LEEEYENLLK ASFERMDHLR QLQNIIQATS REIMWINDCE EEELLYDWSD
KNTNIAQKQE AFSIRMSQLE VKEKELNKLK QESDQLVLNQ HPASDKIEAY MDTLQTQWSW
ILQITKCIDV HLKENAAYFQ FFEEAQSTEA YLKGLQDSIR KKYPCDKNMP LQHLLEQIKE
LEKEREKILE YKRQVQNLVN KSKKIVQLKP RNPDYRSNKP IILRALCDYK QDQKIVHKGD
ECILKDNNER SKWYVTGPGG VDMLVPSVGL IIPPPNPLAV DLSCKIEQYY EAILALWNQL
YINMKSLVSW HYCMIDIEKI RAMTIAKLKT MRQEDYMKTI ADLELHYQEF IRNSQGSEMF
GDDDKRKIQS QFTDAQKHYQ TLVIQLPGYP QHQTVTTTEI THHGTCQDVN HNKVIETNRE
NDKQETWMLM ELQKIRRQIE HCEGRMTLKN LPLADQGSSH HITVKINELK SVQNDSQAIA
EVLNQLKDML ANFRGSEKYC YLQNEVFGLF QKLENINGVT DGYLNSLCTV RALLQAILQT
EDMLKVYEAR LTEEETVCLD LDKVEAYRCG LKKIKNDLNL KKSLLATMKT ELQKAQQIHS
QTSQQYPLYD LDLGKFGEKV TQLTDRWQRI DKQIDFRLWD LEKQIKQLRN YRDNYQAFCK
WLYDAKRRQD SLESMKFGDS NTVMRFLNEQ KNLHSEISGK RDKSEEVQKI AELCANSIKD
YELQLASYTS GLETLLNIPI KRTMIQSPSG VILQEAADVH ARYIELLTRS GDYYRFLSEM
LKSLEDLKLK NTKIEVLEEE LRLARDANSE NCNKNKFLDQ NLQKYQAECS QFKAKLASLE
ELKRQAELDG KSAKQNLDKC YGQIKELNEK ITRLTYEIED EKRRRKSVED RFDQQKNDYD
QLQKARQCEK ENLGWQKLES EKAIKEKEYE IERLRVLLQE EGTRKREYEN ELAKVRNHYN
EEMSNLRNKY ETEINITKTT IKEISMQKED DSKNLRNQLD RLSRENRDLK DEIVRLNDSI
LQATEQRRRA EENALQQKAC GSEIMQKKQH LEIELKQVMQ QRSEDNARHK QSLEEAAKTI
QDKNKEIERL KAEFQEEAKR RWEYENELSK VRNNYDEEII SLKNQFETEI NITKTTIHQL
TMQKEEDTSG YRAQIDNLTR ENRSLSEEIK RLKNTLTQTT ENLRRVEEDI QQQKATGSEV
SQRKQQLEVE LRQVTQMRTE ESVRYKQSLD DAAKTIQDKN KEIERLKQLI DKETNDRKCL
EDENARLQRV QYDLQKANSS ATETINKLKV QEQELTRLRI DYERVSQERT VKDQDITRFQ
NSLKELQLQK QKVEEELNRL KRTASEDSCK RKKLEEELEG MRRSLKEQAI KITNLTQQLE
QASIVKKRSE DDLRQQRDVL DGHLREKQRT QEELRRLSSE VEALRRQLLQ EQESVKQAHL
RNEHFQKAIE DKSRSLNESK IEIERLQSLT ENLTKEHLML EEELRNLRLE YDDLRRGRSE
ADSDKNATIL ELRSQLQISN NRTLELQGLI NDLQRERENL RQEIEKFQKQ ALEASNRIQE
SKNQCTQVVQ ERESLLVKIK VLEQDKARLQ RLEDELNRAK STLEAETRVK QRLECEKQQI
QNDLNQWKTQ YSRKEEAIRK IESEREKSER EKNSLRSEIE RLQAEIKRIE ERCRRKLEDS
TRETQSQLET ERSRYQREID KLRQRPYGSH RETQTECEWT VDTSKLVFDG LRKKVTAMQL
YECQLIDKTT LDKLLKGKKS VEEVASEIQP FLRGAGSIAG ASASPKEKYS LVEAKRKKLI
SPESTVMLLE AQAATGGIID PHRNEKLTVD SAIARDLIDF DDRQQIYAAE KAITGFDDPF
SGKTVSVSEA IKKNLIDRET GMRLLEAQIA SGGVVDPVNS VFLPKDVALA RGLIDRDLYR
SLNDPRDSQK NFVDPVTKKK VSYVQLKERC RIEPHTGLLL LSVQKRSMSF QGIRQPVTVT
ELVDSGILRP STVNELESGQ ISYDEVGERI KDFLQGSSCI AGIYNETTKQ KLGIYEAMKI
GLVRPGTALE LLEAQAATGF IVDPVSNLRL PVEEAYKRGL VGIEFKEKLL SAERAVTGYN
DPETGNIISL FQAMNKELIE KGHGIRLLEA QIATGGIIDP KESHRLPVDI AYKRGYFNEE
LSEILSDPSD DTKGFFDPNT EENLTYLQLK ERCIKDEETG LCLLPLKEKK KQVQTSQKNT
LRKRRVVIVD PETNKEMSVQ EAYKKGLIDY ETFKELCEQE CEWEEITITG SDGSTRVVLV
DRKTGSQYDI QDAIDKGLVD RKFFDQYRSG SLSLTQFADM ISLKNGVGTS SSMGSGVSDD
VFSSSRHESV SKISTISSVR NLTIRSSSFS DTLEESSPIA AIFDTENLEK ISITEGIERG
IVDSITGQRL LEAQACTGGI IHPTTGQKLS LQDAVSQGVI DQDMATRLKP AQKAFIGFEG
VKGKKKMSAA EAVKEKWLPY EAGQRFLEFQ YLTGGLVDPE VHGRISTEEA IRKGFIDGRA
AQRLQDTSSY AKILTCPKTK LKISYKDAIN RSMVEDITGL RLLEAASVSS KGLPSPYNMS
SAPGSRSGSR SGSRSGSRSG SRSGSRRGSF DATGNSSYSY SYSFSSSSIG H
//

MIM 125647
*RECORD*
*FIELD* NO
125647
*FIELD* TI
*125647 DESMOPLAKIN; DSP
DESMOPLAKIN I, INCLUDED; DSPI, INCLUDED;;
DESMOPLAKIN II, INCLUDED; DSPII, INCLUDED
read more*FIELD* TX

DESCRIPTION

Desmosomes are the most common type of intercellular junction in
vertebrate epithelial cells. They are characterized by 2 forms of
interaction with other cellular structures. First, they form membrane
anchorage sites for intermediate-size filaments, which are seen as
electron-dense plaques evident beneath the plasma membrane. Second, a
specific membrane core domain interacts with a corresponding domain of
the plasma membrane of an adjacent cell, apparently mediating
intercellular adhesion in a stable way. The desmosome intermediate
filament complex is thought to impart tensile strength and resilience to
the epithelium. Desmosomal proteins can be divided into 2 groups based
on whether they fractionate with the urea-insoluble 'core' or the
urea-soluble 'plaque' components. Desmoglein (125670) is, for example, a
protein of the core. The main proteins of the plaque comprise the
desmoplakins and plakoglobin (173325).

CLONING

DSPI and DSPII are related proteins of molecular mass 250 kD and 215 kD,
respectively. They are splice variants of the same gene (Green et al.,
1990).

Virata et al. (1992) identified overlapping cDNA clones predicted to
encode a full-length 310-kD polypeptide of 2,677 amino acid residues.
Stappenbeck et al. (1993) and Bornslaeger et al. (1996) made use of
updated information on the desmoplakin protein sequence indicating that
it contains 2,871 amino acids and has a molecular mass of approximately
332 kD.

By RT-PCR, Kazerounian et al. (2002) surveyed the tissue distribution of
several plakin family members, including periplakin (602871), plectin
(601282), desmoplakin, BPAG1 (113810), and envoplakin (601590).
Desmoplakin was expressed at high levels in several tissues, but was
only weakly expressed in adult brain and was not detected in skeletal
muscle or leukocytes.

GENE FUNCTION

Anhalt et al. (1990) discovered an autoimmune disorder, which they
called paraneoplastic pemphigus, associated with lymphoid malignancies,
thymomas, and poorly differentiated sarcomas. Oursler et al. (1992)
demonstrated that autoantibodies against the desmoplakins are an
important component of the humeral autoimmune response in paraneoplastic
pemphigus.

MAPPING

By the study of somatic cell hybrids, Arnemann et al. (1991) mapped the
DSP gene to chromosome 6pter-p21. Olavesen et al. (1997) reported fine
mapping of 39 ESTs on 6p25-p23 that had previously been mapped in
radiation hybrids. Most of the ESTs (31 of 39) were positioned in the
6p24-p23 interval; of these, 8 were located within a single PAC clone.
DSP was the most telomeric of these 8 loci.

MOLECULAR GENETICS

- Keratosis Palmoplantaris Striata II

Armstrong et al. (1999) described the first heterozygous mutation in the
DSP gene, in a family with a striate form of hereditary palmoplantar
keratoderma, designated type II (PPKS2; 612908). The mutation was a
C-to-T transition in exon 4, predicted to result in a premature
termination codon in the N-terminal region of the peptide (125647.0001).
Not only was this the first reported mutation of desmoplakin, but it was
also said to be the first inherited skin disease in which
haploinsufficiency of the structural element was implicated. Armstrong
et al. (1999) concluded that dosage of desmoplakin is critical to the
maintenance of epidermal integrity.

- Dilated Cardiomyopathy with Woolly Hair and Keratoderma

Norgett et al. (2000) described the first recessive human mutation in
the DSP gene, 7901delG (125647.0002), that causes a generalized striate
keratoderma particularly affecting the palmoplantar epidermis, woolly
hair, and dilated left ventricular cardiomyopathy (Carvajal syndrome;
605676). A number of the patients with this syndromic disorder suffered
heart failure in their teenage years, resulting in early morbidity.
Histology of the skin revealed large intercellular spaces and clustering
of desmosomes at the infrequent sites of keratinocyte adhesion.
Immunohistochemistry of skin from the patients showed a perinuclear
localization of keratin in suprabasal keratinocytes, suggesting a
collapsed intermediate filament network.

Uzumcu et al. (2006) described a patient with a recessively inherited
arrhythmogenic dilated cardiomyopathy with left and right ventricular
involvement, epidermolytic palmoplantar keratoderma, and woolly hair
(605676). The patient showed a severe cardiac phenotype with an early
onset and rapid progression to heart failure at 4 years of age. A
homozygous nonsense mutation, R1267X, was found in exon 23 of the
desmoplakin gene (125647.0010), which resulted in an isoform-specific
truncation of the larger desmoplakin isoform I. The loss of most of the
DSPI-specific rod domain and C-terminal area was confirmed by Western
blotting and immunofluorescence. DSP isoform I had been reported to be
an obligate constituent of desmosomes and the only isoform present in
cardiac tissue. Uzumcu et al. (2006) confirmed that it is the major
cardiac isoform, and also showed that several compartments of the heart
have detectable expression of isoform II.

In a Turkish girl with Carvajal syndrome, Rasmussen et al. (2013)
identified homozygosity for a 1-bp deletion in the DSP gene
(125647.0014).

- Skin Fragility-Woolly Hair Syndrome

In 2 probands with skin fragility-woolly hair syndrome (SFWHS; 607655),
Whittock et al. (2002) demonstrated compound heterozygosity for a
nonsense/missense combination of mutations in both patients, cys809 to
ter/asn287 to lys (C809X/N287K; see 125647.0004) and gln664 to
ter/arg2366 to cys (Q664X/R2366C; see 125647.0006), respectively.
Whittock et al. (2002) reported that heterozygous carriers of these
mutations displayed no phenotypic abnormalities. The nonsense mutations
C809X and Q664X would be expected to cause nonsense-mediated mRNA decay
resulting in haploinsufficiency of desmoplakin. Whittock et al. (2002)
concluded that desmoplakin haploinsufficiency can be tolerated in some
cases, but that in combination with a missense mutation on the other
allele, the consequences are a severe genodermatosis with specific
clinical manifestations.

- Familial Arrhythmogenic Right Ventricular Dysplasia 8

In 1 of 16 families observed in northern Italy with arrhythmogenic right
ventricular dysplasia mapped to chromosome 6p24 (ARVD8; 607450),
Rampazzo et al. (2002) found that affected members had a missense
mutation (125647.0003) in exon 7 of the DSP gene.

Rampazzo et al. (2002) noted that DSP, together with junction
plakoglobin (JUP; 173325), anchors to desmosomal cadherins, forming an
ordered array of nontransmembrane proteins, which then bind to keratin
intermediate filaments. The S299R missense mutation (125647.0003) is
located in the N-terminal domain, which is involved in JUP binding and
in clustering of desmosomal cadherin-JUP complexes. Rampazzo et al.
(2002) considered it possible that the absence of skin defects in
heterozygous carriers of the S299R mutation can be explained by
considering that this mutation does not affect DSP-intermediate filament
binding, which, on the contrary, is targeted by other mutations
producing a keratoderma phenotype. In heterozygotes for the S299R
mutation, most desmosomal cadherin-JUP complexes would be defective
because of the dimeric nature of DSP functional molecules. This would
explain the dominant pattern of inheritance in the disease caused by
such a mutation.

In a mutation analysis of 66 probands with ARVD, Yang et al. (2006)
identified 4 variants in DSP: V30M (125467.0011), Q90R, W233X, and
R2834H (125647.0012). To establish a cause and effect relationship
between these DSP missense mutations and ARVD, they performed in vitro
and in vivo analyses of the mutant proteins. Unlike wildtype DSP, the
N-terminal mutants (V30M and Q90R) failed to localize to the cell
membrane in a desmosome-forming cell line and failed to bind to and
coimmunoprecipitate junction plakoglobin. Multiple attempts to generate
N-terminal DSP (V30M and Q90R) cardiac-specific transgenes failed;
analysis of embryos revealed evidence of profound ventricular dilation,
which likely resulted in embryonic lethality. Yang et al. (2006) were
able to develop transgenic (Tg) mice with cardiac-restricted
overexpression of the C-terminal mutant (R2834H) or wildtype DSP.
Whereas mice overexpressing wildtype DSP had no detectable histologic,
morphologic, or functional cardiac changes, the R2834H-Tg mice had
increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid
accumulation, along with ventricular enlargement and cardiac dysfunction
in both ventricles. These mice also displayed interruption of DSP-desmin
interaction at intercalated discs and marked ultrastructural changes of
these discs. The data suggested that DSP expression in cardiomyocytes is
crucial for maintaining cardiac tissue integrity, and that DSP
abnormalities result in ARVD by cardiomyocyte death, changes in lipid
metabolism, and defects in cardiac development.

Rasmussen et al. (2013) studied 4 patients with mutations in the DSP
gene, 3 ARVD patients and 1 patient with Carvajal syndrome. The mutation
carriers had abnormal DSP expression in both myocardial and epidermal
tissue; disease mechanisms included haploinsufficiency,
dominant-negative effects, or both. The authors concluded that because
protein abnormalities in cardiac tissue from patients with desmosomal
cardiomyopathies are also present in their keratinocytes, human
keratinocyte cultures from affected individuals can be used for protein
expression studies and elucidation of molecular disease mechanisms.

- Lethal Acantholytic Epidermolysis Bullosa

Jonkman et al. (2005) reported a patient with severe fragility of skin
and mucous membranes caused by genetic truncation of the desmoplakin
tail. They named the phenotype in this disorder, from which the infant
died at the age of 10 days, 'lethal acantholytic epidermolysis bullosa'
(609638). Skin fragility was accompanied by universal alopecia, neonatal
teeth, and nail loss. The patient died from immense transcutaneous fluid
loss. Histology showed suprabasal clefting and acantholysis throughout
the spinous layer, mimicking pemphigus. Electron microscopy showed
disconnection of keratin intermediate filaments from desmosomes.
Immunofluorescence staining of desmoplakin showed a distinct punctate
intercellular pattern in the patient's skin. Protein analysis showed
expression of truncated desmoplakin polypeptides. Mutation analysis
showed that the patient was a compound heterozygote for 2 DSP mutations,
R1934X (125647.0008) and 6370delTT (125647.0009). Aberrant mRNA
transcripts that predicted premature termination of translation with a
loss of the 3 intermediate filament-binding subdomains in the DP tail
were detected by RT-PCR.

ANIMAL MODEL

Vasioukhin et al. (2001) generated a desmoplakin mouse knockout and
showed that epidermal integrity requires desmoplakin. Mechanical
stresses to DP-null skin cause intercellular separations. The number of
epidermal desmosomes in DP-null skin was similar to wildtype, but they
lacked keratin filaments, which compromise their function. DP-null
keratinocytes have few desmosomes in vitro, and are unable to undergo
actin reorganization and membrane sealing during epithelial sheet
formation. Adherens junctions were also reduced. In vitro, DP transgene
expression rescued these defects. Desmoplakin is therefore required for
assembly of functional desmosomes, maintaining cytoskeletal
architecture, and reinforcing membrane attachments essential for stable
intercellular adhesion.

*FIELD* AV
.0001
KERATOSIS PALMOPLANTARIS STRIATA II
DSP, GLN331TER

In a large kindred with a striate subtype of palmoplantar keratoderma
and demonstrated linkage of the disorder to 6p21 (612908), Armstrong et
al. (1999) identified a heterozygous C-to-T transition at nucleotide
1323 in exon 4, converting a glutamine residue to a stop codon (gln331
to ter). The mutation was not detected on cDNA screening. The absence of
RNA transcribed from the mutant allele in keratinocytes suggested that
nonsense-mediated mRNA decay was operative in this kindred, resulting in
a functionally null allele and desmoplakin haploinsufficiency.

.0002
CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR AND KERATODERMA
DSP, 1-BP DEL, 7901G

Norgett et al. (2000) described the first recessive human mutation in
the DSP gene, 7901delG, which causes a generalized striate keratoderma
particularly affecting the palmoplantar epidermis, woolly hair, and a
dilated left ventricular cardiomyopathy (605676). The mutation was
predicted to cause a premature stop codon to be inserted 18 codons
downstream from the deletion and to result in the truncation of the C
domain in the tail region of the protein. This region of the desmoplakin
protein interacts with intermediate filaments to anchor them to the
desmosome (Bornslaeger et al., 1996). All tested affected members of 3
families from Ecuador were homozygous for the mutation. While
desmoplakin-null mice die early in development, the human 7901delG
mutation is not embryonic lethal. The authors hypothesized that the tail
domain of desmoplakin is not required for establishing tissue
architecture during development.

.0003
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8
DSP, SER299ARG

In affected members of an Italian family with arrhythmogenic right
ventricular dysplasia mapping to 6p24 (607450), Rampazzo et al. (2002)
identified a ser299-to-arg (S299R) missense mutation in exon 7 of the
DSP gene.

.0004
SKIN FRAGILITY-WOOLLY HAIR SYNDROME
DSP, ASN287LYS

In a patient with skin fragility-woolly hair syndrome (607655), Whittock
et al. (2002) reported compound heterozygosity for mutations in the DSP
gene: an 861G-T transversion in exon 7, resulting in an asn287-to-lys
(N287K) substitution, and a 2427T-A transversion in exon 17, resulting
in a cys809-to-ter (C809X; 125647.0005) substitution. The C809X allele
resulted in nonsense-mediated mRNA decay and only the N287K DSP gene
product was expressed, resulting in a severe keratoderma phenotype.

.0005
SKIN FRAGILITY-WOOLLY HAIR SYNDROME
DSP, CYS809TER

See 125647.0004 and Whittock et al. (2002).

.0006
SKIN FRAGILITY-WOOLLY HAIR SYNDROME
DSP, ARG2366CYS

In a patient with skin fragility-woolly hair syndrome (607655), Whittock
et al. (2002) reported compound heterozygosity for mutations in the DSP
gene: a 7096C-T transition in exon 24 that resulted in an arg2366-to-cys
(R2366C) amino acid change, and a 1990C-T transition in exon 15 that
resulted in a gln664-to-ter amino acid change (Q664X; 125647.0007). The
Q664X allele resulted in nonsense-mediated mRNA decay and only the
R2366C DSP gene product was expressed, resulting in a severe keratoderma
phenotype. The R2366C change occurred within the intermediate filament
carboxy B domain. Specifically, this changed a charged residue at
position 22 of the third 38-amino acid repeat. This sequence is highly
conserved among the other plakin molecules plectin (601282), bullous
pemphigoid antigen-1 (113810), and epiplakin (607553), with a consensus
motif of GXRXLE (Ruhrberg and Watt, 1997; Fujiwara et al., 2001). This
residue may be involved with the bundle formation that binds to
intermediate filament proteins. The substitution of a cysteine would be
expected to affect intrachain and/or interchain disulfide bonding, thus
changing the tertiary structure of the C-terminal domain.

.0007
SKIN FRAGILITY-WOOLLY HAIR SYNDROME
DSP, GLN664TER

See 125647.0006 and Whittock et al. (2002).

.0008
EPIDERMOLYSIS BULLOSA, LETHAL ACANTHOLYTIC
DSP, ARG1934TER

In an infant with lethal acantholytic epidermolysis bullosa (609638),
Jonkman et al. (2005) found compound heterozygosity for 2 mutations in
exon 24 of the DSP gene. A 6079C-T transition that resulted in a change
of arg1934 to a stop codon (R1934X) was inherited from the father, and a
deletion of 2 nucleotides (125647.0009) was inherited from the mother.
The heterozygous parents were nonconsanguineous and phenotypically
normal.

.0009
EPIDERMOLYSIS BULLOSA, LETHAL ACANTHOLYTIC
DSP, 6360TT DEL

The infant described by Jonkman et al. (2005) with lethal acantholytic
epidermolysis bullosa (609638) carried a 2-nucleotide deletion,
6370delTT, on the maternal DSP allele. This mutation was predicted to
cause a frameshift resulting in novel sequence beginning at amino acid
2031 and premature termination at position 2058. See also 125647.0008.

.0010
CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR AND KERATODERMA
DSP, ARG1267TER

In the child of consanguineous Turkish parents with recessively
inherited arrhythmogenic dilated cardiopathy with left and right
ventricular involvement, epidermolytic palmoplantar keratoderma, and
woolly hair (605676), Uzumcu et al. (2006) found a homozygous nonsense
mutation, arg1267 to stop (R1267X), in exon 23 of the desmoplakin gene,
which resulted in an isoform-specific truncation of the larger isoform I
of desmoplakin. The amino acid substitution arose from a 3799C-T
transition.

.0011
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8
DSP, VAL30MET

In a patient with arrhythmogenic right ventricular
dysplasia/cardiomyopathy (607450), Yang et al. (2006) identified an
88G-A transition in the DSP gene, resulting in a val30-to-met (V30M)
substitution.

.0012
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8
DSP, ARG2834HIS

In a patient with arrhythmogenic right ventricular
dysplasia/cardiomyopathy (607450), Yang et al. (2006) identified an
8501G-A transition in the DSP gene, resulting in an arg2834-to-his
(R2834H) substitution.

.0013
SKIN FRAGILITY-WOOLLY HAIR SYNDROME
DSP, ARG2366HIS

In 5 members from 2 related Saudi families diagnosed with skin
fragility-woolly hair syndrome (607665), Al-Owain et al. (2011)
identified homozygosity for a 7097G-A transition in the DSP gene,
resulting in an arg2366-to-his (R2366H) substitution. The parents were
heterozygous for the mutation, which was not found in 400 chromosomes
from healthy control individuals of the same ethnic group. No cardiac
symptoms were reported and there was no family history of sudden death.
A normal echocardiographic evaluation was found in 2 of those affected
who were 4 and 7 years of age; formal cardiac work-up was refused in the
other 3 affected members, aged 3, 14, and 16 years. Because
cardiomyopathy sometimes occurs later in life in the syndrome of dilated
cardiomyopathy with woolly hair and keratoderma (605676), Al-Owain et
al. (2011) suggested that the current diagnosis was not beyond doubt.

.0014
CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR AND KERATODERMA
DSP, 1-BP DEL, 7780T

In a Turkish girl with woolly hair and palmoplantar keratoderma who had
congestive heart failure requiring cardiac transplantation at age 12
years (Carvajal syndrome; 605676), Rasmussen et al. (2013) identified
homozygosity for a 1-bp deletion (c.7780delT) in the last exon of the
DSP gene, causing a frameshift predicted to result in a premature
termination codon (Ser2594PhefsTer8). Her unaffected first-cousin
parents and 2 sibs were heterozygous for the deletion. Expression
studies in cultured keratinocytes and immunohistochemistry of epidermal
and myocardial tissue in the proband and her mother indicated that the
homozygous patient incorporated mutant DSP into myocardial and epidermal
desmosomes, whereas the mutant DSP was almost entirely degraded in the
healthy heterozygous mother, in whom expression of wildtype DSP was
reduced by 50% compared to controls.

*FIELD* RF
1. Al-Owain, M.; Wakil, S.; Shareef, F.; Al-Fatani, A.; Hamadah, E.;
Haider, M.; Al-Hindi, H.; Awaji, A.; Khalifa, O.; Baz, B.; Ramadhan,
R.; Meyer, B.: Novel homozygous mutation in DSP causing skin fragility-woolly
hair syndrome: report of a large family and review of the desmoplakin-related
phenotypes. Clin. Genet. 80: 50-58, 2011.

2. Anhalt, G. J.; Kim, S.; Stanley, J. R.; Korman, N. J.; Jabs, D.
A.; Kory, M.; Izumi, H.; Ratrie, H., III; Mutasim, D.; Ariss-Abdo,
L.; Labib, R. S.: Paraneoplastic pemphigus: an autoimmune mucocutaneous
disease associated with neoplasia. New Eng. J. Med. 323: 1729-1735,
1990.

3. Armstrong, D. K.; McKenna, K. E.; Purkis, P. E.; Green, K. J.;
Eady, R. A. J.; Leigh, I. M.; Hughes, A. E.: Haploinsufficiency of
desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum.
Molec. Genet. 8: 143-148, 1999. Note: Erratum: Hum. Molec. Genet.
8: 943 only, 1999.

4. 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.

5. Bornslaeger, E. A.; Corcoran, C. M.; Stappenbeck, T. S.; Green,
K. J.: Breaking the connection: displacement of the desmosomal plaque
protein desmoplakin from cell-cell interfaces disrupts anchorage of
intermediate filament bundles and alters intercellular junction assembly. J.
Cell Biol. 134: 985-1001, 1996.

6. Fujiwara, S.; Takeo, N.; Otani, Y.; Parry, D. A. D.; Kunimatsu,
M.; Lu, R.; Sasaki, M.; Matsuo, N.; Khaleduzzaman, M.; Yoshioka, H.
: Epiplakin, a novel member of the plakin family originally identified
as a 450-kDa human epidermal autoantigen: structure and tissue localization. J.
Biol. Chem. 276: 13340-13347, 2001.

7. Green, K. J.; Parry, D. A.; Steinert, P. M.; Virata, M. L.; Wagner,
R. M.; Angst, B. D.; Nilles, L. A.: Structure of the human desmoplakins:
implications for function in the desmosomal plaque. J. Biol. Chem. 265:
2603-2612, 1990. Note: Erratum: J. Biol. Chem. 265: 11406-11407, 1990.

8. Jonkman, M. F.; Pasmooij, A. M. G.; Pasmans, S. G. M. A.; van den
Berg, M. P.; ter Horst, H. J.; Timmer, A.; Pas, H. H.: Loss of desmoplakin
tail causes lethal acantholytic epidermolysis bullosa. Am. J. Hum.
Genet. 77: 653-660, 2005.

9. Kazerounian, S.; Uitto, J.; Aho, S.: Unique role for the periplakin
tail in intermediate filament association: specific binding to keratin
8 and vimentin. Exp. Derm. 11: 428-438, 2002.

10. Norgett, E. E.; Hatsell, S. J.; Carvajal-Huerta, L.; Ruiz Cabezas,
J.-C.; Common, J.; Purkis, P. E.; Whittock, N.; Leigh, I. M.; Stevens,
H. P.; Kelsell, D. P.: Recessive mutation in desmoplakin disrupts
desmoplakin-intermediate filament interactions and causes dilated
cardiomyopathy, woolly hair and keratoderma. Hum. Molec. Genet. 9:
2761-2766, 2000.

11. Olavesen, M. G.; Bentley, E.; Mason, R. V. F.; Stephens, R. J.;
Ragoussis, J.: Fine mapping of 39 ESTs on human chromosome 6p23-p25. Genomics 46:
303-306, 1997.

12. Oursler, J. R.; Labib, R. S.; Ariss-Abdo, L.; Burke, T.; O'Keefe,
E. J.; Anhalt, G. J.: Human autoantibodies against desmoplakins in
paraneoplastic pemphigus. J. Clin. Invest. 89: 1775-1782, 1992.

13. Rampazzo, A.; Nava, A.; Malacrida, S.; Beffagna, G.; Bauce, B.;
Rossi, V.; Zimbello, R.; Simionati, B.; Basso, C.; Thiene, G.; Towbin,
J. A.; Danieli, G. A.: Mutation in human desmoplakin domain binding
to plakoglobin causes a dominant form of arrhythmogenic right ventricular
cardiomyopathy. Am. J. Hum. Genet. 71: 1200-1206, 2002.

14. Rasmussen, T. B.; Hansen, J.; Nissen, P. H. Palmfeldt, J.; Dalager,
S.; Jensen, U. B.; Kim, W. Y.; Heickendorff, L.; Molgaard, H.; Jensen,
H. K.; Sorensen, K. E.; Baandrup, U. T.; Bross, P.; Mogensen, J.:
Protein expression studies of desmoplakin mutations in cardiomyopathy
patients reveal different molecular disease mechanisms. Clin. Genet. 84:
20-30, 2013.

15. Ruhrberg, C.; Watt, F. M.: The plakin family: versatile organizers
of cytoskeletal architecture. Curr. Opin. Genet. Dev. 7: 392-397,
1997.

16. Stappenbeck, T. S.; Bornslaeger, E. A.; Corcoran, C. M.; Luu,
H. H.; Virata, M. L.; Green, K. J.: Functional analysis of desmoplakin
domains: specification of the interaction with keratin versus vimentin
intermediate filament networks. J. Cell Biol. 123: 691-705, 1993.

17. Uzumcu, A.; Norgett, E. E.; Dindar, A.; Uyguner, O.; Nisli, K.;
Kayserili, H.; Sahin, S. E.; Dupont, E.; Severs, N. J.; Leigh, I.
M.; Yuksel-Apak, M.; Kelsell, D. P.; Wollnik, B.: Loss of desmoplakin
isoform 1 causes early onset cardiomyopathy and heart failure in a
Naxos-like syndrome. (Letter) J. Med. Genet. 43: e5, 2006. Note:
Electronic Article.

18. Vasioukhin, V.; Bowers, E.; Bauer, C.; Degenstein, L.; Fuchs,
E.: Desmoplakin is essential in epidermal sheet formation. Nature
Cell Biol. 3: 1076-1085, 2001.

19. Virata, M. L. A.; Wagner, R. M.; Parry, D. A. D.; Green, K. J.
: Molecular structure of the human desmoplakin I and II amino terminus. Proc.
Nat. Acad. Sci. 89: 544-548, 1992.

20. Whittock, N. V.; Wan, H.; Morley, S. M.; Garzon, M. C.; Kristal,
L.; Hyde, P.; McLean, W. H. I.; Pulkkinen, L.; Uitto, J.; Christiano,
A. M.; Eady, R. A. J.; McGrath, J. A.: Compound heterozygosity for
non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly
hair syndrome. J. Invest. Derm. 118: 232-238, 2002.

21. Yang, Z.; Bowles, N. E.; Scherer, S. E.; Taylor, M. D.; Kearney,
D. L.; Ge, S.; Nadvoretskiy, V. V.; DeFreitas, G.; Carabello, B.;
Brandon, L. I.; Godsel, L. M.; Green, K. J.; Saffitz, J. E.; Li, H.;
Danieli, G. A.; Calkins, H.; Marcus, F.; Towbin, J. A.: Desmosomal
dysfunction due to mutations in desmoplakin causes arrhythmogenic
right ventricular dysplasia/cardiomyopathy. Circ. Res. 99: 646-655,
2006.

*FIELD* CN
Marla J. F. O'Neill - updated: 8/8/2013
Carol A. Bocchini - updated: 3/19/2012
Victor A. McKusick - updated: 9/26/2006
Victor A. McKusick - updated: 3/9/2006
Victor A. McKusick - updated: 10/5/2005
Patricia A. Hartz - updated: 10/7/2003
Gary A. Bellus - updated: 3/25/2003
Victor A. McKusick - updated: 12/23/2002
Victor A. McKusick - updated: 2/14/2002
George E. Tiller - updated: 2/23/2001
Victor A. McKusick - updated: 3/23/2000
Victor A. McKusick - updated: 2/17/1999
Victor A. McKusick - updated: 2/4/1998

*FIELD* CD
Victor A. McKusick: 6/20/1991

*FIELD* ED
carol: 08/09/2013
tpirozzi: 8/8/2013
terry: 3/19/2012
carol: 3/19/2012
wwang: 1/14/2011
carol: 7/13/2009
carol: 7/10/2009
carol: 10/13/2006
terry: 9/26/2006
alopez: 3/15/2006
alopez: 3/14/2006
terry: 3/9/2006
alopez: 10/7/2005
terry: 10/5/2005
alopez: 11/23/2004
alopez: 9/16/2004
carol: 3/17/2004
mgross: 10/7/2003
carol: 7/25/2003
alopez: 3/25/2003
carol: 1/10/2003
cwells: 12/27/2002
terry: 12/23/2002
cwells: 2/21/2002
cwells: 2/15/2002
terry: 2/14/2002
alopez: 2/23/2001
terry: 3/23/2000
carol: 9/13/1999
carol: 6/16/1999
terry: 5/6/1999
carol: 2/26/1999
mgross: 2/25/1999
mgross: 2/23/1999
mgross: 2/22/1999
terry: 2/17/1999
mark: 2/5/1998
terry: 2/4/1998
mark: 6/9/1996
warfield: 3/28/1994
carol: 7/23/1992
carol: 7/7/1992
carol: 6/19/1992
supermim: 3/16/1992
carol: 6/24/1991

MIM 605676
*RECORD*
*FIELD* NO
605676
*FIELD* TI
#605676 CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR AND KERATODERMA; DCWHK
;;CARVAJAL SYNDROME;;
read morePALMOPLANTAR KERATODERMA WITH LEFT VENTRICULAR CARDIOMYOPATHY AND
WOOLLY HAIR
*FIELD* TX
A number sign (#) is used with this entry because dilated cardiomyopathy
with woolly hair and keratoderma (DCWHK) is caused by homozygous
mutation in the DSP gene (125647), which encodes desmoplakin, on
chromosome 6p24.

CLINICAL FEATURES

Carvajal-Huerta (1998) described 18 patients with a confirmation of
epidermolytic palmoplantar keratoderma, woolly hair, and dilated
cardiomyopathy, examined clinically and histologically in Ecuador
between 1970 and 1997. Cardiologic examinations were performed in 12 of
the patients. The patients were born with woolly hair. Around the first
year, palmoplantar keratoderma and other keratotic signs appeared. The
first cardiac abnormalities were exclusively electrocardiographic and
occurred in asymptomatic patients. In these patients, dilation of the
left ventricle, together with alterations in muscle contractility, was
observed. The dilated cardiomyopathy sometimes led to congestive heart
failure and death.

Rasmussen et al. (2013) studied a Turkish girl who presented at 8 years
of age with congestive heart failure, woolly hair, and palmoplantar
keratoderma, consistent with a diagnosis of Carvajal syndrome.
Transthoracic echocardiogram showed biventricular dilation and a left
ventricular ejection fraction of 15%, and she underwent cardiac
transplantation at age 12 years. The explanted heart showed severe
dilation of all 4 chambers, thinned myocardium, extensive interstitial
replacement fibrosis, and hypertrophy of cardiomyocytes, without fatty
infiltrations or inflammatory changes. Her first-cousin parents and 2
sibs were unaffected.

INHERITANCE

Autosomal recessive inheritance was considered likely in the Ecuadorian
families examined by Carvajal-Huerta (1998). The patients were
distributed in 6 families; in 2 families, parental consanguinity was
documented.

MOLECULAR GENETICS

Desmosomes are major cell adhesion junctions, particularly prominent in
the epidermis and cardiac tissue and are important for the rigidity and
strength of the cells (Green et al., 1990; for a review, see the entry
for desmoplakin, 125647). The desmosome consists of several proteins, of
which desmoplakin (DSP) is the most abundant. Mutations in the DSP gene
can cause isolated autosomal dominant palmoplantar keratoderma
(Armstrong et al., 1999). Norgett et al. (2000) described the first
recessive human desmoplakin gene mutation, 7901delG (125647.0002), which
causes a generalized striate keratoderma particularly affecting the
palmoplantar epidermis, woolly hair, and a dilated left ventricular
cardiomyopathy. All tested affected members of 3 families from Ecuador
were homozygous for this mutation, which produces a premature stop codon
leading to a truncated desmoplakin protein missing the C domain of the
tail region. Cardiologic investigation, including electrocardiographic
and echocardiographic examinations, of a number of the affected family
members was reported by Carvajal-Huerta (1998). A number of the patients
with this syndromic disorder suffered heart failure in their teenage
years, resulting in early morbidity. Histology of the skin revealed
large intercellular spaces and clustering of desmosomes at the
infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin
from the patients showed a perinuclear localization of keratin in
suprabasal keratinocytes, suggesting a collapsed intermediate filament
network. The study demonstrated the importance of desmoplakin in the
attachment of intermediate filaments to the desmosome. Desmoplakin-null
mice die in early development (Gallicano et al., 1998); in contrast, the
truncated protein due to the homozygous 7901delG mutation in humans is
not embryonic lethal. The authors hypothesized that the tail domain of
desmoplakin is not required for establishing tissue architecture during
development.

Mutation in the gene encoding another desmosomal component, plakoglobin
(173325), causes Naxos disease (601214), which is also characterized by
woolly hair and a clinically distinct keratoderma and heart disorder.

Both Naxos disease and dilated cardiomyopathy with woolly hair and
keratoderma are autosomal recessive, whereas most of the hereditary
dilated cardiomyopathies are autosomal dominant (Schonberger and
Seidman, 2001). Naxos disease maps to 17q21.

In a Turkish girl with Carvajal syndrome, Rasmussen et al. (2013)
identified homozygosity for a 1-bp deletion in the DSP gene
(125647.0014). Her unaffected first-cousin parents and 2 sibs were
heterozygous for the mutation.

*FIELD* RF
1. Armstrong, D. K.; McKenna, K. E.; Purkis, P. E.; Green, K. J.;
Eady, R. A. J.; Leigh, I. M.; Hughes, A. E.: Haploinsufficiency of
desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum.
Molec. Genet. 8: 143-148, 1999. Note: Erratum: Hum. Molec. Genet.
8: 943 only, 1999.

2. Carvajal-Huerta, L.: Epidermolytic palmoplantar keratoderma with
woolly hair and dilated cardiomyopathy. J. Am. Acad. Derm. 39: 418-421,
1998.

3. Gallicano, G. I.; Kouklis, P.; Bauer, C.; Yin, M.; Vasioukhin,
V.; Degenstein, L.; Fuchs, E.: Desmoplakin is required early in development
for assembly of desmosomes and cytoskeletal linkage. J. Cell Biol. 143:
2009-2022, 1998.

4. Green, K. J.; Parry, D. A.; Steinert, P. M.; Virata, M. L.; Wagner,
R. M.; Angst, B. D.; Nilles, L. A.: Structure of the human desmoplakins:
implications for function in the desmosomal plaque. J. Biol. Chem. 265:
2603-2612, 1990. Note: Erratum: J. Biol. Chem. 265: 11406-11407, 1990.

5. Norgett, E. E.; Hatsell, S. J.; Carvajal-Huerta, L.; Ruiz Cabezas,
J.-C.; Common, J.; Purkis, P. E.; Whittock, N.; Leigh, I. M.; Stevens,
H. P.; Kelsell, D. P.: Recessive mutation in desmoplakin disrupts
desmoplakin-intermediate filament interactions and causes dilated
cardiomyopathy, woolly hair and keratoderma. Hum. Molec. Genet. 9:
2761-2766, 2000.

6. Rasmussen, T. B.; Hansen, J.; Nissen, P. H. Palmfeldt, J.; Dalager,
S.; Jensen, U. B.; Kim, W. Y.; Heickendorff, L.; Molgaard, H.; Jensen,
H. K.; Sorensen, K. E.; Baandrup, U. T.; Bross, P.; Mogensen, J.:
Protein expression studies of desmoplakin mutations in cardiomyopathy
patients reveal different molecular disease mechanisms. Clin. Genet. 84:
20-30, 2013.

7. 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.

*FIELD* CN
Marla J. F. O'Neill - updated: 8/8/2013
Victor A. McKusick - updated: 12/23/2002
Victor A. McKusick - updated: 8/30/2001

*FIELD* CD
George E. Tiller: 2/23/2001

*FIELD* ED
carol: 08/13/2013
carol: 8/9/2013
tpirozzi: 8/8/2013
terry: 12/20/2012
terry: 4/5/2005
alopez: 3/25/2003
alopez: 3/5/2003
cwells: 12/27/2002
terry: 12/23/2002
cwells: 9/20/2001
cwells: 9/18/2001
terry: 8/30/2001
alopez: 2/26/2001
alopez: 2/23/2001

MIM 607450
*RECORD*
*FIELD* NO
607450
*FIELD* TI
#607450 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8; ARVD8
;;ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 8; ARVC8
read more*FIELD* TX
A number sign (#) is used with this entry because arrhythmogenic right
ventricular dysplasia-8 is caused by mutation in the gene encoding
desmoplakin (DSP; 125647).

For a phenotypic description and a discussion of genetic heterogeneity
of ARVD, see 107970.

MAPPING

Rampazzo et al. (2002) reported on a genome scan in an Italian family in
which the disorder appeared unlinked to any of the previously reported
ARVD loci. Significantly positive linkage was detected for several
markers on the short arm of chromosome 6 (maximum lod = 4.32 at theta =
0 for marker D6S309). All patients in the family shared a common
haplotype. Since the novel 6p24 locus described by Rampazzo et al.
(2002) was the eighth reported for ARVD, they named the locus ARVD8.
Penetrance was approximately 50%.

POPULATION GENETICS

ARVD8 is probably an infrequent form of ARVD, at least in northeast
Italy; among 16 families in which Rampazzo et al. (2002) firmly
established linkage with ARVD loci, this was the only family linked to
6p.

MOLECULAR GENETICS

In the family with ARVD mapping to 6p, Rampazzo et al. (2002) identified
a mutation in the desmoplakin gene (125647.0003). They focused on the
DSP gene because a homozygous DSP nonsense mutation had been reported to
cause a biventricular dilated cardiomyopathy associated with keratoderma
and woolly hair (605676) in an Ecuadorian family.

Rampazzo et al. (2002) noted that the involvement of DSP and JUP
(173325) in 2 different ARVD clinical phenotypes, ARVD8 and Naxos
disease (601214), suggests that some ARVDs may result from defects in
intercellular connections. Mutations in the cardiac ryanodine receptor
(RYR2; 180902) cause dominant ARVD2 (600996), thus supporting the
hypothesis of a key pathogenic role played by altered intracellular
calcium concentration in these disorders.

*FIELD* RF
1. Rampazzo, A.; Nava, A.; Malacrida, S.; Beffagna, G.; Bauce, B.;
Rossi, V.; Zimbello, R.; Simionati, B.; Basso, C.; Thiene, G.; Towbin,
J. A.; Danieli, G. A.: Mutation in human desmoplakin domain binding
to plakoglobin causes a dominant form of arrhythmogenic right ventricular
cardiomyopathy. Am. J. Hum. Genet. 71: 1200-1206, 2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, right ventricular;
Ventricular arrhythmia (PVC, VT, and VF);
Sudden cardiac death;
Heart failure

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the desmoplakin gene (DSP, 125647.0003)

*FIELD* CD
Kelly A. Przylepa: 3/6/2008

*FIELD* ED
joanna: 03/06/2008
joanna: 3/6/2008

*FIELD* CD
Victor A. McKusick: 12/27/2002

*FIELD* ED
carol: 09/19/2013
carol: 6/15/2010
carol: 1/10/2003
cwells: 12/27/2002

MIM 607655
*RECORD*
*FIELD* NO
607655
*FIELD* TI
#607655 SKIN FRAGILITY-WOOLLY HAIR SYNDROME; SFWHS
*FIELD* TX
A number sign (#) is used with this entry because the skin
read morefragility-woolly hair syndrome is caused by homozygous or compound
heterozygous mutation in the desmoplakin gene (DSP; 125647) on
chromosome 6p24.

CLINICAL FEATURES

Whittock et al. (2002) reported 2 unrelated individuals with an
autosomal recessive genodermatosis characterized by focal and diffuse
palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs,
and woolly hair with varying degrees of alopecia. They referred to this
disorder as skin fragility-woolly hair syndrome (SFWHS). The phenotype
of SFWHS is similar to dilated cardiomyopathy with woolly hair and
keratoderma (DCWHK; 605676), another recessive disorder due to
desmoplakin mutations, but is significantly different in that DCWHK
lacks persistent skin fragility with neonatal onset and SFWHS lacks
cardiomyopathy. The combination of desmoplakin haploinsufficiency and a
missense mutation resulted in a painful keratoderma on the hands and
feet with recurrent secondary infection. Occasionally, there was more
widespread trauma-induced 'sloughing' of the skin. In contrast to other
genodermatoses such as epidermolysis bullosa simplex (see 131800),
patients with SFWHS did not appear to improve with age. Unlike other
forms of keratoderma, this disorder was disabling, and patients required
a wheelchair for mobility.

BIOCHEMICAL FEATURES

Immunohistochemistry of skin biopsies from both affected individuals
with SFWHS reported by Whittock et al. (2002) revealed that desmoplakin
was located not only at the cell periphery but also in the cytoplasm. In
addition, electron microscopy demonstrated acantholysis throughout all
layers of the skin, focal detachment of desmosomes into the
intercellular spaces, and perinuclear condensation of the suprabasal
keratin intermediate filament network.

MOLECULAR GENETICS

In 2 probands with SFWHS, Whittock et al. (2002) performed mutation
screening of desmoplakin and demonstrated compound heterozygosity for a
nonsense/missense combination of mutations in both patients, cys809 to
ter/asn287 to lys (C809X/N287K; see 125647.0004) and gln664 to
ter/arg2366 to cys (Q664X/R2366C; see 125647.0006), respectively.
Mutations in desmoplakin also cause some cases of the autosomal dominant
skin disorder striate palmoplantar keratoderma (see 148700), which is
characterized clinically by linear and focal hyperkeratosis of the palms
and soles. Whittock et al. (2002) reported that heterozygous carriers of
DSP C809X, N287K, Q664X, or R2366C mutations displayed no phenotypic
abnormalities. The nonsense mutations C809X and Q664X would be expected
to cause nonsense-mediated mRNA decay resulting in haploinsufficiency of
desmoplakin. Whittock et al. (2002) concluded that desmoplakin
haploinsufficiency can be tolerated in some cases, but that in
combination with a missense mutation on the other allele, the
consequences are a severe genodermatosis with specific clinical
manifestations.

*FIELD* RF
1. Whittock, N. V.; Wan, H.; Morley, S. M.; Garzon, M. C.; Kristal,
L.; Hyde, P.; McLean, W. H. I.; Pulkkinen, L.; Uitto, J.; Christiano,
A. M.; Eady, R. A. J.; McGrath, J. A.: Compound heterozygosity for
non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly
hair syndrome. J. Invest. Derm. 118: 232-238, 2002.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Normal

SKIN, NAILS, HAIR:
[Skin];
Fragility with blistering (neonatal onset);
Palmoplantar keratosis with erythema and scale;
Hyperkeratotic plaques on trunk and limbs;
HISTOLOGY:;
Peripheral and cytoplasmic desmoplakin staining (immunohistochemistry)
ELECTRON MICROSCOPY:;
Acantholysis throughout all layers of the skin;
Focal detachment of desmosomes into the intercellular spaces;
Perinuclear condensation of the suprabasal keratin intermediate filament
network;
[Nails];
Nail dystrophy;
[Hair];
Alopecia;
Woolly hair;
Sparse eyelashes;
Sparse eyebrows

MOLECULAR BASIS:
Caused by mutations in the desmoplakin gene (DSP, 125647.0004)

*FIELD* CD
Gary A. Bellus: 3/27/2003

*FIELD* ED
joanna: 10/16/2003

*FIELD* CD
Gary A. Bellus: 3/25/2003

*FIELD* ED
carol: 03/19/2012
alopez: 3/25/2003

MIM 609638
*RECORD*
*FIELD* NO
609638
*FIELD* TI
#609638 EPIDERMOLYSIS BULLOSA, LETHAL ACANTHOLYTIC
;;EBLA
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is
read morecaused by mutation in the desmoplakin gene (DSP; 125647).

CLINICAL FEATURES

Jonkman et al. (2005) described a male infant with severe fragility of
skin and mucous membranes in whom rapidly progressive generalized
epidermolysis had begun during delivery. The area of epidermolysis
progressed from 30% to 70% within the first day and to 90% by the fifth
day. Large sheets of skin were detached, leaving superficial, not
bleeding, dull, intense red wound surfaces. The child lost profuse
amounts of fluid from the extensive skin erosions. The skin fragility
was accompanied by universal alopecia and nail loss, and 3 triangular
neonatal teeth were present. Death occurred at 10 days of age due to
immense transcutaneous fluid loss. Histopathology of the skin showed
suprabasal clefting, leaving basal cells attached to the blister floor
like a row of tombstones. The spinous layer showed spongiosis (widening
of the intercellular space) and acantholysis, looking like a
'dilapidated brick wall,' which extended into hair follicles and eccrine
ducts. The histopathology mimicked that of pemphigus vulgaris (169610).
Electron microscopic examination of the skin revealed that the level of
cleavage was intracellular, between the inner dense plaque of the
desmosome and the cytoskeleton. Immunofluorescence staining of
desmosomal proteins showed a distinct punctate intercellular pattern in
the patient's skin. Jonkman et al. (2005) designated the phenotype
lethal acantholytic epidermolysis bullosa.

MOLECULAR GENETICS

The observation in their patient that the keratin intermediate filaments
were disconnected from the inner dense plaque, similar to desmoplakin
knockout mice and patients with skin fragility-woolly hair syndrome
(607655), led Jonkman et al. (2005) to screen the DSP gene (125647) for
mutations. Mutation screening of genomic DNA demonstrated compound
heterozygosity for 2 mutations in exon 24 of the DSP gene. A premature
termination mutation (R1934X; 125647.0008) was inherited from the
father, and a 2-bp deletion (6370delTT; 125647.0009) was inherited from
the mother. Aberrant mRNA transcripts that predicted premature
termination of translation with loss of the 3 intermediate
filament-binding subdomains in the desmoplakin tail were detected by
RT-PCR. Protein analysis showed expression of truncated desmoplakin
polypeptides.

*FIELD* RF
1. Jonkman, M. F.; Pasmooij, A. M. G.; Pasmans, S. G. M. A.; van den
Berg, M. P.; ter Horst, H. J.; Timmer, A.; Pas, H. H.: Loss of desmoplakin
tail causes lethal acantholytic epidermolysis bullosa. Am. J. Hum.
Genet. 77: 653-660, 2005.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Teeth];
Neonatal teeth

GENITOURINARY:
[External genitalia, male];
Phimosis, secondary to epidermolysis

SKELETAL:
[Hands];
Pseudosyndactyly;
Tapered distal phalanges;
[Feet];
Widely spaced toes

SKIN, NAILS, HAIR:
[Skin];
Progressive generalized skin erosions;
Cutis aplasia;
HISTOLOGY:;
Suprabasal clefting;
Acantholysis;
ELECTRON MICROSCOPY:;
Disconnection of keratin intermediate filaments from desmosomes;
[Nails];
Nail loss;
[Hair];
Universal alopecia

MISCELLANEOUS:
Neonatal death

MOLECULAR BASIS:
Caused by mutation in the desmoplakin gene (DSP, 125647.0008).

*FIELD* CD
Kelly A. Przylepa: 11/29/2006

*FIELD* ED
joanna: 12/21/2007
joanna: 9/12/2007
alopez: 10/7/2005

*FIELD* CD
Victor A. McKusick: 10/7/2005

*FIELD* ED
alopez: 03/15/2006
alopez: 10/17/2005
alopez: 10/7/2005

MIM 612908
*RECORD*
*FIELD* NO
612908
*FIELD* TI
#612908 KERATOSIS PALMOPLANTARIS STRIATA II; PPKS2
;;KERATODERMA, PALMOPLANTAR, STRIATE FORM II; KPPS2;;
read moreSTRIATE PALMOPLANTAR KERATODERMA II; SPPK2
*FIELD* TX
A number sign (#) is used with this entry because keratosis
palmoplantaris striata II is caused by mutation in the gene encoding
desmoplakin (DSP; 125647).

For a discussion of genetic heterogeneity of the striate form of
palmoplantar keratoderma, see PPKS1 (148700).

CLINICAL FEATURES

Armstrong et al. (1999) studied a large family segregating autosomal
dominant striate palmoplantar keratoderma. Affected individuals
developed palmoplantar thickening in the first or early second decade of
life. This was most prominent in a linear pattern along the flexor
aspects of the fingers and over pressure points on the soles. There was
a tendency to a coexistent milder, more diffuse background palmoplantar
thickening in some. Individuals were prone to develop fissuring but
there was no history of frank blister formation. There were no skin
changes outside the palmoplantar areas, and no abnormalities of hair,
nails, or teeth were noted.

MAPPING

In a large family segregating the striate form of palmoplantar
keratoderma, Armstrong et al. (1999) excluded linkage to the 18q21
region where the PPKS1 locus had been mapped. By microsatellite typing
with markers mapping to other regions, they demonstrated linkage of the
disorder (PPKS2) to 6p21 with a maximum lod score of 10.67.

MOLECULAR GENETICS

In affected members of a large family with a striate form of
palmoplantar keratoderma mapping to chromosome 6p21, Armstrong et al.
(1999) identified heterozygosity for a mutation in the DSP gene
(125647.0001). The authors stated that this was the first inherited skin
disease in which haploinsufficiency of the structural element was
implicated.

*FIELD* RF
1. Armstrong, D. K.; McKenna, K. E.; Purkis, P. E.; Green, K. J.;
Eady, R. A. J.; Leigh, I. M.; Hughes, A. E.: Haploinsufficiency of
desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum.
Molec. Genet. 8: 143-148, 1999. Note: Erratum: Hum. Molec. Genet.
8: 943 only, 1999.

*FIELD* CD
Carol A. Bocchini: 7/13/2009

*FIELD* ED
terry: 07/13/2009
carol: 7/13/2009