Full text data of PKP1
PKP1
[Confidence: low (only semi-automatic identification from reviews)]
Plakophilin-1 (Band 6 protein; B6P)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Plakophilin-1 (Band 6 protein; B6P)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13835
ID PKP1_HUMAN Reviewed; 747 AA.
AC Q13835; O00645; Q14CA0; Q15152;
DT 23-JAN-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=Plakophilin-1;
DE AltName: Full=Band 6 protein;
DE Short=B6P;
GN Name=PKP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Epidermis;
RX PubMed=7527055;
RA Hatzfeld M., Kristjansson G.I., Plessmann U., Weber K.;
RT "Band 6 protein, a major constituent of desmosomes from stratified
RT epithelia, is a novel member of the armadillo multigene family.";
RL J. Cell Sci. 107:2259-2270(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9369526; DOI=10.1007/s004410050956;
RA Schmidt A., Langbein L., Rode M., Praetzel S., Zimbelmann R.,
RA Franke W.W.;
RT "Plakophilins 1a and 1b: widespread nuclear proteins recruited in
RT specific epithelial cells as desmosomal plaque components.";
RL Cell Tissue Res. 290:481-499(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [5]
RP INVOLVEMENT IN ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME, AND
RP FUNCTION.
RX PubMed=9326952; DOI=10.1038/ng1097-240;
RA McGrath J.A., McMillan J.R., Shemanko C.S., Runswick S.K., Leigh I.M.,
RA Lane E.B., Garrod D.R., Eady R.A.J.;
RT "Mutations in the plakophilin 1 gene result in ectodermal
RT dysplasia/skin fragility syndrome.";
RL Nat. Genet. 17:240-244(1997).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 244-721, AND DOMAINS ARM
RP REPEATS.
RX PubMed=15663951; DOI=10.1016/j.jmb.2004.11.048;
RA Choi H.-J., Weis W.I.;
RT "Structure of the armadillo repeat domain of plakophilin 1.";
RL J. Mol. Biol. 346:367-376(2005).
CC -!- FUNCTION: Seems to play a role in junctional plaques. Contributes
CC to epidermal morphogenesis.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Nucleus. Cell junction,
CC desmosome.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2; Synonyms=1b;
CC IsoId=Q13835-1; Sequence=Displayed;
CC Name=1; Synonyms=1a;
CC IsoId=Q13835-2; Sequence=VSP_006735;
CC -!- TISSUE SPECIFICITY: Isoform 2 is widely expressed. Isoform 1 is
CC expressed in stratified squamous, complex, glandular duct and
CC bladder epithelia.
CC -!- DISEASE: Ectodermal dysplasia-skin fragility syndrome (EDSFS)
CC [MIM:604536]: A form of ectodermal dysplasia, a heterogeneous
CC group of disorders due to abnormal development of two or more
CC ectodermal structures. Characterized by features of both cutaneous
CC fragility and congenital ectodermal dysplasia affecting skin, hair
CC and nails. There is no evidence of significant abnormalities in
CC other epithelia or tissues. Desmosomes in the skin are small and
CC poorly formed with widening of keratinocyte intercellular spaces
CC and perturbed desmosome/keratin intermediate filament
CC interactions. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the beta-catenin family.
CC -!- SIMILARITY: Contains 9 ARM repeats.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X79293; CAA55881.1; -; mRNA.
DR EMBL; Z34974; CAA84426.1; -; mRNA.
DR EMBL; Z73677; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z73678; CAA98022.1; -; Genomic_DNA.
DR EMBL; CH471067; EAW91350.1; -; Genomic_DNA.
DR EMBL; BC114571; AAI14572.1; -; mRNA.
DR PIR; S60712; S60712.
DR RefSeq; NP_000290.2; NM_000299.3.
DR RefSeq; NP_001005337.1; NM_001005337.2.
DR UniGene; Hs.497350; -.
DR PDB; 1XM9; X-ray; 2.80 A; A=244-721.
DR PDBsum; 1XM9; -.
DR ProteinModelPortal; Q13835; -.
DR SMR; Q13835; 244-721.
DR IntAct; Q13835; 5.
DR STRING; 9606.ENSP00000263946; -.
DR PhosphoSite; Q13835; -.
DR DMDM; 20138951; -.
DR PaxDb; Q13835; -.
DR PRIDE; Q13835; -.
DR Ensembl; ENST00000263946; ENSP00000263946; ENSG00000081277.
DR Ensembl; ENST00000352845; ENSP00000295597; ENSG00000081277.
DR Ensembl; ENST00000367324; ENSP00000356293; ENSG00000081277.
DR GeneID; 5317; -.
DR KEGG; hsa:5317; -.
DR UCSC; uc001gwd.3; human.
DR CTD; 5317; -.
DR GeneCards; GC01P201252; -.
DR HGNC; HGNC:9023; PKP1.
DR HPA; HPA027221; -.
DR HPA; HPA027589; -.
DR MIM; 601975; gene.
DR MIM; 604536; phenotype.
DR neXtProt; NX_Q13835; -.
DR Orphanet; 158668; Epidermolysis bullosa simplex due to plakophilin deficiency.
DR PharmGKB; PA33356; -.
DR eggNOG; NOG262883; -.
DR HOGENOM; HOG000060193; -.
DR HOVERGEN; HBG096389; -.
DR InParanoid; Q13835; -.
DR KO; K10387; -.
DR OMA; NYGTTSR; -.
DR OrthoDB; EOG7QVM31; -.
DR PhylomeDB; Q13835; -.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; Q13835; -.
DR EvolutionaryTrace; Q13835; -.
DR GeneWiki; PKP1; -.
DR GenomeRNAi; 5317; -.
DR NextBio; 20566; -.
DR PRO; PR:Q13835; -.
DR ArrayExpress; Q13835; -.
DR Bgee; Q13835; -.
DR CleanEx; HS_PKP1; -.
DR Genevestigator; Q13835; -.
DR GO; GO:0030057; C:desmosome; NAS:UniProtKB.
DR GO; GO:0005882; C:intermediate filament; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0019215; F:intermediate filament binding; NAS:UniProtKB.
DR GO; GO:0005521; F:lamin binding; IDA:BHF-UCL.
DR GO; GO:0004871; F:signal transducer activity; TAS:ProtInc.
DR GO; GO:0030280; F:structural constituent of epidermis; NAS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; NAS:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0045110; P:intermediate filament bundle assembly; IDA:BHF-UCL.
DR GO; GO:0007275; P:multicellular organismal development; IEA:UniProtKB-KW.
DR Gene3D; 1.25.10.10; -; 2.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000225; Armadillo.
DR InterPro; IPR028432; Plakophilin-1.
DR InterPro; IPR028435; Plakophilin/d_Catenin.
DR PANTHER; PTHR10372; PTHR10372; 1.
DR PANTHER; PTHR10372:SF3; PTHR10372:SF3; 1.
DR Pfam; PF00514; Arm; 1.
DR SMART; SM00185; ARM; 6.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50176; ARM_REPEAT; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell junction;
KW Complete proteome; Developmental protein; Ectodermal dysplasia;
KW Nucleus; Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 747 Plakophilin-1.
FT /FTId=PRO_0000064284.
FT REPEAT 243 274 ARM 1.
FT REPEAT 275 316 ARM 2.
FT REPEAT 317 359 ARM 3.
FT REPEAT 360 415 ARM 4.
FT REPEAT 416 463 ARM 5.
FT REPEAT 525 556 ARM 6.
FT REPEAT 557 603 ARM 7.
FT REPEAT 604 649 ARM 8.
FT REPEAT 650 713 ARM 9.
FT VAR_SEQ 412 432 Missing (in isoform 1).
FT /FTId=VSP_006735.
FT VARIANT 116 116 R -> H (in dbSNP:rs34626929).
FT /FTId=VAR_033526.
FT VARIANT 161 161 C -> Y (in dbSNP:rs34704938).
FT /FTId=VAR_033527.
FT VARIANT 196 196 I -> V (in dbSNP:rs35507614).
FT /FTId=VAR_033528.
FT VARIANT 415 415 G -> D (in dbSNP:rs1626370).
FT /FTId=VAR_053811.
FT VARIANT 463 463 A -> V (in dbSNP:rs10920171).
FT /FTId=VAR_062171.
FT CONFLICT 154 154 R -> G (in Ref. 1; CAA55881).
FT CONFLICT 216 222 PPISCNK -> RHLLQQ (in Ref. 1; CAA55881).
FT CONFLICT 462 462 V -> E (in Ref. 1; CAA55881).
FT CONFLICT 496 496 Q -> K (in Ref. 1; CAA55881).
FT CONFLICT 506 506 T -> P (in Ref. 1; CAA55881).
FT CONFLICT 553 553 L -> S (in Ref. 1; CAA55881).
FT HELIX 247 255
FT HELIX 260 272
FT HELIX 279 285
FT HELIX 288 295
FT HELIX 301 315
FT HELIX 319 327
FT HELIX 331 338
FT HELIX 344 358
FT STRAND 360 362
FT HELIX 364 378
FT HELIX 381 384
FT HELIX 400 411
FT HELIX 438 444
FT HELIX 450 464
FT HELIX 472 482
FT TURN 483 485
FT HELIX 486 489
FT HELIX 493 499
FT HELIX 539 544
FT HELIX 546 558
FT HELIX 562 575
FT STRAND 579 581
FT HELIX 582 591
FT HELIX 597 603
FT HELIX 609 623
FT HELIX 626 628
FT HELIX 629 635
FT HELIX 637 642
FT HELIX 654 669
FT HELIX 674 679
FT HELIX 682 686
FT HELIX 689 693
FT HELIX 698 709
FT STRAND 712 714
SQ SEQUENCE 747 AA; 82861 MW; 60C1BCCC50AB4E6F CRC64;
MNHSPLKTAL AYECFQDQDN STLALPSDQK MKTGTSGRQR VQEQVMMTVK RQKSKSSQSS
TLSHSNRGSM YDGLADNYNY GTTSRSSYYS KFQAGNGSWG YPIYNGTLKR EPDNRRFSSY
SQMENWSRHY PRGSCNTTGA GSDICFMQKI KASRSEPDLY CDPRGTLRKG TLGSKGQKTT
QNRYSFYSTC SGQKAIKKCP VRPPSCASKQ DPVYIPPISC NKDLSFGHSR ASSKICSEDI
ECSGLTIPKA VQYLSSQDEK YQAIGAYYIQ HTCFQDESAK QQVYQLGGIC KLVDLLRSPN
QNVQQAAAGA LRNLVFRSTT NKLETRRQNG IREAVSLLRR TGNAEIQKQL TGLLWNLSST
DELKEELIAD ALPVLADRVI IPFSGWCDGN SNMSREVVDP EVFFNATGCL RKRLGMRELL
ALVPQRATSS RVNLSSADAG RQTMRNYSGL IDSLMAYVQN CVAASRCDDK SVENCMCVLH
NLSYRLDAEV PTRYRQLEYN ARNAYTEKSS TGCFSNKSDK MMNNNYDCPL PEEETNPKGS
GWLYHSDAIR TYLNLMGKSK KDATLEACAG ALQNLTASKG LMSSGMSQLI GLKEKGLPQI
ARLLQSGNSD VVRSGASLLS NMSRHPLLHR VMGNQVFPEV TRLLTSHTGN TSNSEDILSS
ACYTVRNLMA SQPQLAKQYF SSSMLNNIIN LCRSSASPKA AEAARLLLSD MWSSKELQGV
LRQQGFDRNM LGTLAGANSL RNFTSRF
//
ID PKP1_HUMAN Reviewed; 747 AA.
AC Q13835; O00645; Q14CA0; Q15152;
DT 23-JAN-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=Plakophilin-1;
DE AltName: Full=Band 6 protein;
DE Short=B6P;
GN Name=PKP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Epidermis;
RX PubMed=7527055;
RA Hatzfeld M., Kristjansson G.I., Plessmann U., Weber K.;
RT "Band 6 protein, a major constituent of desmosomes from stratified
RT epithelia, is a novel member of the armadillo multigene family.";
RL J. Cell Sci. 107:2259-2270(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9369526; DOI=10.1007/s004410050956;
RA Schmidt A., Langbein L., Rode M., Praetzel S., Zimbelmann R.,
RA Franke W.W.;
RT "Plakophilins 1a and 1b: widespread nuclear proteins recruited in
RT specific epithelial cells as desmosomal plaque components.";
RL Cell Tissue Res. 290:481-499(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [5]
RP INVOLVEMENT IN ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME, AND
RP FUNCTION.
RX PubMed=9326952; DOI=10.1038/ng1097-240;
RA McGrath J.A., McMillan J.R., Shemanko C.S., Runswick S.K., Leigh I.M.,
RA Lane E.B., Garrod D.R., Eady R.A.J.;
RT "Mutations in the plakophilin 1 gene result in ectodermal
RT dysplasia/skin fragility syndrome.";
RL Nat. Genet. 17:240-244(1997).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 244-721, AND DOMAINS ARM
RP REPEATS.
RX PubMed=15663951; DOI=10.1016/j.jmb.2004.11.048;
RA Choi H.-J., Weis W.I.;
RT "Structure of the armadillo repeat domain of plakophilin 1.";
RL J. Mol. Biol. 346:367-376(2005).
CC -!- FUNCTION: Seems to play a role in junctional plaques. Contributes
CC to epidermal morphogenesis.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Nucleus. Cell junction,
CC desmosome.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2; Synonyms=1b;
CC IsoId=Q13835-1; Sequence=Displayed;
CC Name=1; Synonyms=1a;
CC IsoId=Q13835-2; Sequence=VSP_006735;
CC -!- TISSUE SPECIFICITY: Isoform 2 is widely expressed. Isoform 1 is
CC expressed in stratified squamous, complex, glandular duct and
CC bladder epithelia.
CC -!- DISEASE: Ectodermal dysplasia-skin fragility syndrome (EDSFS)
CC [MIM:604536]: A form of ectodermal dysplasia, a heterogeneous
CC group of disorders due to abnormal development of two or more
CC ectodermal structures. Characterized by features of both cutaneous
CC fragility and congenital ectodermal dysplasia affecting skin, hair
CC and nails. There is no evidence of significant abnormalities in
CC other epithelia or tissues. Desmosomes in the skin are small and
CC poorly formed with widening of keratinocyte intercellular spaces
CC and perturbed desmosome/keratin intermediate filament
CC interactions. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the beta-catenin family.
CC -!- SIMILARITY: Contains 9 ARM repeats.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X79293; CAA55881.1; -; mRNA.
DR EMBL; Z34974; CAA84426.1; -; mRNA.
DR EMBL; Z73677; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z73678; CAA98022.1; -; Genomic_DNA.
DR EMBL; CH471067; EAW91350.1; -; Genomic_DNA.
DR EMBL; BC114571; AAI14572.1; -; mRNA.
DR PIR; S60712; S60712.
DR RefSeq; NP_000290.2; NM_000299.3.
DR RefSeq; NP_001005337.1; NM_001005337.2.
DR UniGene; Hs.497350; -.
DR PDB; 1XM9; X-ray; 2.80 A; A=244-721.
DR PDBsum; 1XM9; -.
DR ProteinModelPortal; Q13835; -.
DR SMR; Q13835; 244-721.
DR IntAct; Q13835; 5.
DR STRING; 9606.ENSP00000263946; -.
DR PhosphoSite; Q13835; -.
DR DMDM; 20138951; -.
DR PaxDb; Q13835; -.
DR PRIDE; Q13835; -.
DR Ensembl; ENST00000263946; ENSP00000263946; ENSG00000081277.
DR Ensembl; ENST00000352845; ENSP00000295597; ENSG00000081277.
DR Ensembl; ENST00000367324; ENSP00000356293; ENSG00000081277.
DR GeneID; 5317; -.
DR KEGG; hsa:5317; -.
DR UCSC; uc001gwd.3; human.
DR CTD; 5317; -.
DR GeneCards; GC01P201252; -.
DR HGNC; HGNC:9023; PKP1.
DR HPA; HPA027221; -.
DR HPA; HPA027589; -.
DR MIM; 601975; gene.
DR MIM; 604536; phenotype.
DR neXtProt; NX_Q13835; -.
DR Orphanet; 158668; Epidermolysis bullosa simplex due to plakophilin deficiency.
DR PharmGKB; PA33356; -.
DR eggNOG; NOG262883; -.
DR HOGENOM; HOG000060193; -.
DR HOVERGEN; HBG096389; -.
DR InParanoid; Q13835; -.
DR KO; K10387; -.
DR OMA; NYGTTSR; -.
DR OrthoDB; EOG7QVM31; -.
DR PhylomeDB; Q13835; -.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; Q13835; -.
DR EvolutionaryTrace; Q13835; -.
DR GeneWiki; PKP1; -.
DR GenomeRNAi; 5317; -.
DR NextBio; 20566; -.
DR PRO; PR:Q13835; -.
DR ArrayExpress; Q13835; -.
DR Bgee; Q13835; -.
DR CleanEx; HS_PKP1; -.
DR Genevestigator; Q13835; -.
DR GO; GO:0030057; C:desmosome; NAS:UniProtKB.
DR GO; GO:0005882; C:intermediate filament; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0019215; F:intermediate filament binding; NAS:UniProtKB.
DR GO; GO:0005521; F:lamin binding; IDA:BHF-UCL.
DR GO; GO:0004871; F:signal transducer activity; TAS:ProtInc.
DR GO; GO:0030280; F:structural constituent of epidermis; NAS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; NAS:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0045110; P:intermediate filament bundle assembly; IDA:BHF-UCL.
DR GO; GO:0007275; P:multicellular organismal development; IEA:UniProtKB-KW.
DR Gene3D; 1.25.10.10; -; 2.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000225; Armadillo.
DR InterPro; IPR028432; Plakophilin-1.
DR InterPro; IPR028435; Plakophilin/d_Catenin.
DR PANTHER; PTHR10372; PTHR10372; 1.
DR PANTHER; PTHR10372:SF3; PTHR10372:SF3; 1.
DR Pfam; PF00514; Arm; 1.
DR SMART; SM00185; ARM; 6.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50176; ARM_REPEAT; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell junction;
KW Complete proteome; Developmental protein; Ectodermal dysplasia;
KW Nucleus; Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 747 Plakophilin-1.
FT /FTId=PRO_0000064284.
FT REPEAT 243 274 ARM 1.
FT REPEAT 275 316 ARM 2.
FT REPEAT 317 359 ARM 3.
FT REPEAT 360 415 ARM 4.
FT REPEAT 416 463 ARM 5.
FT REPEAT 525 556 ARM 6.
FT REPEAT 557 603 ARM 7.
FT REPEAT 604 649 ARM 8.
FT REPEAT 650 713 ARM 9.
FT VAR_SEQ 412 432 Missing (in isoform 1).
FT /FTId=VSP_006735.
FT VARIANT 116 116 R -> H (in dbSNP:rs34626929).
FT /FTId=VAR_033526.
FT VARIANT 161 161 C -> Y (in dbSNP:rs34704938).
FT /FTId=VAR_033527.
FT VARIANT 196 196 I -> V (in dbSNP:rs35507614).
FT /FTId=VAR_033528.
FT VARIANT 415 415 G -> D (in dbSNP:rs1626370).
FT /FTId=VAR_053811.
FT VARIANT 463 463 A -> V (in dbSNP:rs10920171).
FT /FTId=VAR_062171.
FT CONFLICT 154 154 R -> G (in Ref. 1; CAA55881).
FT CONFLICT 216 222 PPISCNK -> RHLLQQ (in Ref. 1; CAA55881).
FT CONFLICT 462 462 V -> E (in Ref. 1; CAA55881).
FT CONFLICT 496 496 Q -> K (in Ref. 1; CAA55881).
FT CONFLICT 506 506 T -> P (in Ref. 1; CAA55881).
FT CONFLICT 553 553 L -> S (in Ref. 1; CAA55881).
FT HELIX 247 255
FT HELIX 260 272
FT HELIX 279 285
FT HELIX 288 295
FT HELIX 301 315
FT HELIX 319 327
FT HELIX 331 338
FT HELIX 344 358
FT STRAND 360 362
FT HELIX 364 378
FT HELIX 381 384
FT HELIX 400 411
FT HELIX 438 444
FT HELIX 450 464
FT HELIX 472 482
FT TURN 483 485
FT HELIX 486 489
FT HELIX 493 499
FT HELIX 539 544
FT HELIX 546 558
FT HELIX 562 575
FT STRAND 579 581
FT HELIX 582 591
FT HELIX 597 603
FT HELIX 609 623
FT HELIX 626 628
FT HELIX 629 635
FT HELIX 637 642
FT HELIX 654 669
FT HELIX 674 679
FT HELIX 682 686
FT HELIX 689 693
FT HELIX 698 709
FT STRAND 712 714
SQ SEQUENCE 747 AA; 82861 MW; 60C1BCCC50AB4E6F CRC64;
MNHSPLKTAL AYECFQDQDN STLALPSDQK MKTGTSGRQR VQEQVMMTVK RQKSKSSQSS
TLSHSNRGSM YDGLADNYNY GTTSRSSYYS KFQAGNGSWG YPIYNGTLKR EPDNRRFSSY
SQMENWSRHY PRGSCNTTGA GSDICFMQKI KASRSEPDLY CDPRGTLRKG TLGSKGQKTT
QNRYSFYSTC SGQKAIKKCP VRPPSCASKQ DPVYIPPISC NKDLSFGHSR ASSKICSEDI
ECSGLTIPKA VQYLSSQDEK YQAIGAYYIQ HTCFQDESAK QQVYQLGGIC KLVDLLRSPN
QNVQQAAAGA LRNLVFRSTT NKLETRRQNG IREAVSLLRR TGNAEIQKQL TGLLWNLSST
DELKEELIAD ALPVLADRVI IPFSGWCDGN SNMSREVVDP EVFFNATGCL RKRLGMRELL
ALVPQRATSS RVNLSSADAG RQTMRNYSGL IDSLMAYVQN CVAASRCDDK SVENCMCVLH
NLSYRLDAEV PTRYRQLEYN ARNAYTEKSS TGCFSNKSDK MMNNNYDCPL PEEETNPKGS
GWLYHSDAIR TYLNLMGKSK KDATLEACAG ALQNLTASKG LMSSGMSQLI GLKEKGLPQI
ARLLQSGNSD VVRSGASLLS NMSRHPLLHR VMGNQVFPEV TRLLTSHTGN TSNSEDILSS
ACYTVRNLMA SQPQLAKQYF SSSMLNNIIN LCRSSASPKA AEAARLLLSD MWSSKELQGV
LRQQGFDRNM LGTLAGANSL RNFTSRF
//
MIM
601975
*RECORD*
*FIELD* NO
601975
*FIELD* TI
*601975 PLAKOPHILIN 1; PKP1
*FIELD* TX
CLONING
Plakoglobin (JUP; 173325) was first identified as a protein of the
read moredesmosomal type of cell junction. It is a component of the plaque, i.e.,
that part of the desmosome in the cytoplasm with which the intermediate
filaments interact. Another desmosomal component, plakophilin,
originally known as band 6 protein, was cloned and sequenced in human
and bovine by Hatzfeld et al. (1994) and Heid et al. (1994).
Schmidt et al. (1999) determined that there are at least 2 isoforms of
the PKP1 protein: PKP1a with 726 amino acids and PKP1b with 747 amino
acids. PKP1b is located exclusively in nuclei, whereas PKP1a is located
in nuclei as well as in desmosomal plaques of stratified and complex
epithelia.
GENE STRUCTURE
Schmidt et al. (1999) found that the primary PKP1 transcript spans
approximately 50 kb and contains 15 exons, and identified exon 7 as the
alternatively used exon, leading to splice variant PKP1b. Each mRNA
splice form can occur in 2 polyadenylation forms of approximately 2.7
and 5.3 kb.
GENE FUNCTION
Using immunohistochemistry and quantitative electron microscopy,
McMillan et al. (2003) examined suprabasal desmosomes from 3
PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous
acceptor splice site mutation, and 5 healthy control subjects. Compared
with those in controls, desmosomes in PKP1-null patients were reduced
dramatically both in size (49%) and frequency (61%) in the lower
suprabasal layers (P less than 0.01). In the lower suprabasal
compartment of the heterozygous carrier, corresponding reductions were
37% and 20%, respectively (P less than 0.01). Surprisingly, in the
PKP1-null patients' upper suprabasal layer, desmosome size was larger
(59%, P less than 0.01) than the control value, and showed increased
desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal
layer desmosome frequency in PKP1-null patients was similar to that seen
in the lower suprabasal compartment but reduced by 43% compared to
controls. The carrier showed no difference in the upper suprabasal layer
desmosome size and frequency compared with the controls (P greater than
0.05). The PKP1-null patients showed poorly developed inner and outer
desmosomal plaques. Thus, both the patients and unaffected carrier
showed reductions in the lower suprabasal layer desmosome size and
number, despite only PKP1-null patients exhibiting any phenotype. These
findings attest to the molecular recruiting and stabilizing roles of
PKP1 in desmosome formation, particularly in the lower suprabasal
compartment.
MAPPING
Cowley et al. (1997) used PCR analysis of monochromosomal somatic cell
hybrids to map the PKP1 gene to chromosome 1; fluorescence in situ
hybridization showed that the gene resides on the distal portion of 1q.
By fluorescence in situ hybridization and analysis of a somatic cell
hybrid mapping panel, Bonne et al. (1998) refined the mapping of the
PKP1 gene to 1q32.
MOLECULAR GENETICS
Members of the armadillo protein gene family, which includes plakoglobin
and beta-catenin (116806), have important functions in cytoskeleton/cell
membrane interactions. These proteins may act as linker molecules at
adherens junctions and desmosomes at the plasma membrane; in addition,
they may have pivotal roles in signal transduction pathways and
significant effects on cell behavior during development. McGrath et al.
(1997) described the first human mutations in 1 of these dual function
proteins. A 6-year-old boy with the ectodermal dysplasia/skin fragility
syndrome (604536) showed complete absence of immunostaining for
plakophilin-1 in the skin and was found to be a compound heterozygote
for 2 nonsense mutations of the PKP1 gene (601975.0001). Clinically,
there were features of both cutaneous fragility and congenital
ectodermal dysplasia affecting skin, hair, and nails. There was no
evidence of significant abnormalities in other epithelia or tissues.
Desmosomes in the skin were small and poorly formed with widening of
keratinocyte intercellular spaces and perturbed desmosome/keratin
intermediate filament interactions. The molecular findings and clinical
observations in this patient attested to the dual importance of
plakophilin-1 in both cutaneous cell-cell adhesion and epidermal
morphogenesis.
*FIELD* AV
.0001
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, GLN304TER
McGrath et al. (1997) found compound heterozygosity for 2 nonsense
mutations in the PKP1 gene in a 6-year-old boy with the ectodermal
dysplasia/skin fragility syndrome (604536). One allele of the PKF1 gene
carried a C-to-T transition that changed a glutamine residue (CAG) to a
stop codon (TAG). This mutation was present in the father also. The
other allele of the proband carried a 28-bp internal duplication
mutation (601975.0002), causing a frameshift and a stop codon 66 bp
downstream from the site of the insertion. This mutation was present in
the mother. The paternal mutation, gln304 to ter (Q304X), was present
within the first repeat domain, while the maternal duplication and
downstream premature termination codon resided within the third domain.
There was no family history of skin blistering or other significant
abnormalities and the parents were unrelated. At birth, the proband's
skin was lobster pink generally, with blistering on the soles. Over the
first 48 hours, he developed more severe blistering and desquamation on
the face, limbs, and buttocks. His hair was short and sparse, and the
nails were thickened and dystrophic. Subsequently, his skin continued to
show fragility, with trauma-induced tearing and blisters on the pressure
points of the soles after prolonged standing or walking.
.0002
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, 28-BP DUP, NT1132
See 601975.0001 and McGrath et al. (1997), who referred to this mutation
as 1132ins28.
.0003
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, IVS6, A-T, -2
Whittock et al. (2000) reported a homozygous splice site mutation
(1233-2 A-T) in a 17-year-old male with the ectodermal dysplasia/skin
fragility syndrome (604536). The clinical features comprised skin
erosions, dystrophic nails, sparse hair, and painful thickening and
cracking of palms and soles.
*FIELD* SA
Schmidt et al. (1997)
*FIELD* RF
1. Bonne, S.; van Hengel, J.; van Roy, F.: Chromosomal mapping of
human armadillo genes belonging to the p120(ctn)/plakophilin subfamily. Genomics 51:
452-454, 1998.
2. 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.
3. Hatzfeld, M.; Kristjansson, G. I.; Plessmann, U.; Weber, K.: Band
6 protein, a major constituent of desmosomes from stratified epithelia,
is a novel member of the armadillo multigene family. J. Cell Sci. 107:
2259-2270, 1994.
4. Heid, H. W.; Schmidt, A.; Zimbelmann, R.; Schafer, S.; Winter-Simanowski,
S.; Stumpp, S.; Keith, M.; Figge, U.; Schnolzer, M.; Franke, W. W.
: Cell type-specific desmosomal plaque proteins of the plakoglobin
family: plakophilin 1 (band 6 protein). Differentiation 58: 113-131,
1994.
5. McGrath, J. A.; McMillan, J. R.; Shemanko, C. S.; Runswick, S.
K.; Leigh, I. M.; Lane, E. B.; Garrod, D. R.; Eady, R. A. J.: Mutations
in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility
syndrome. Nature Genet. 17: 240-244, 1997.
6. McMillan, J. R.; Haftek, M.; Akiyama, M.; South, A. P.; Perrot,
H.; McGrath, J. A.; Eady, R. A. J.; Shimizu, H.: Alterations in desmosome
size and number coincide with the loss of keratinocyte cohesion in
skin with homozygous and heterozygous defects in the desmosomal protein
plakophilin 1. J. Invest Derm. 121: 96-103, 2003.
7. Schmidt, A.; Langbein, L.; Pratzel, S.; Rode, M.; Rackwitz, H.-R.;
Franke, W. W.: Plakophilin 3--a novel cell-type-specific desmosomal
plaque protein. Differentiation 64: 291-306, 1999.
8. Schmidt, A.; Langbein, L.; Rode, M.; Pratzel, S.; Zimbelmann, R.;
Franke, W. W.: Plakophilins 1a and 1b: widespread nuclear proteins
recruited in specific epithelial cells as desmosomal plaque components. Cell
Tissue Res. 290: 481-499, 1997.
9. Whittock, N. V.; Haftek, M.; Angoulvant, N.; Wolf, F.; Perrot,
H.; Eady, R. A. J.; McGrath, J. A.: Genomic amplification of the
human plakophilin 1 gene and detection of a new mutation in ectodermal
dysplasia/skin fragility syndrome. J. Invest. Derm. 115: 368-374,
2000.
*FIELD* CN
Gary A. Bellus - updated: 09/05/2003
Gary A. Bellus - updated: 4/6/2001
Carol A. Bocchini - updated: 1/18/2001
Sheryl A. Jankowski - updated: 11/2/1999
*FIELD* CD
Victor A. McKusick: 9/5/1997
*FIELD* ED
alopez: 09/05/2003
alopez: 9/5/2003
cwells: 4/25/2001
cwells: 4/12/2001
cwells: 4/6/2001
mcapotos: 3/15/2001
carol: 3/14/2001
carol: 1/18/2001
carol: 2/10/2000
psherman: 11/2/1999
terry: 7/29/1998
mark: 10/1/1997
dholmes: 9/30/1997
jenny: 9/30/1997
terry: 9/26/1997
jenny: 9/5/1997
*RECORD*
*FIELD* NO
601975
*FIELD* TI
*601975 PLAKOPHILIN 1; PKP1
*FIELD* TX
CLONING
Plakoglobin (JUP; 173325) was first identified as a protein of the
read moredesmosomal type of cell junction. It is a component of the plaque, i.e.,
that part of the desmosome in the cytoplasm with which the intermediate
filaments interact. Another desmosomal component, plakophilin,
originally known as band 6 protein, was cloned and sequenced in human
and bovine by Hatzfeld et al. (1994) and Heid et al. (1994).
Schmidt et al. (1999) determined that there are at least 2 isoforms of
the PKP1 protein: PKP1a with 726 amino acids and PKP1b with 747 amino
acids. PKP1b is located exclusively in nuclei, whereas PKP1a is located
in nuclei as well as in desmosomal plaques of stratified and complex
epithelia.
GENE STRUCTURE
Schmidt et al. (1999) found that the primary PKP1 transcript spans
approximately 50 kb and contains 15 exons, and identified exon 7 as the
alternatively used exon, leading to splice variant PKP1b. Each mRNA
splice form can occur in 2 polyadenylation forms of approximately 2.7
and 5.3 kb.
GENE FUNCTION
Using immunohistochemistry and quantitative electron microscopy,
McMillan et al. (2003) examined suprabasal desmosomes from 3
PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous
acceptor splice site mutation, and 5 healthy control subjects. Compared
with those in controls, desmosomes in PKP1-null patients were reduced
dramatically both in size (49%) and frequency (61%) in the lower
suprabasal layers (P less than 0.01). In the lower suprabasal
compartment of the heterozygous carrier, corresponding reductions were
37% and 20%, respectively (P less than 0.01). Surprisingly, in the
PKP1-null patients' upper suprabasal layer, desmosome size was larger
(59%, P less than 0.01) than the control value, and showed increased
desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal
layer desmosome frequency in PKP1-null patients was similar to that seen
in the lower suprabasal compartment but reduced by 43% compared to
controls. The carrier showed no difference in the upper suprabasal layer
desmosome size and frequency compared with the controls (P greater than
0.05). The PKP1-null patients showed poorly developed inner and outer
desmosomal plaques. Thus, both the patients and unaffected carrier
showed reductions in the lower suprabasal layer desmosome size and
number, despite only PKP1-null patients exhibiting any phenotype. These
findings attest to the molecular recruiting and stabilizing roles of
PKP1 in desmosome formation, particularly in the lower suprabasal
compartment.
MAPPING
Cowley et al. (1997) used PCR analysis of monochromosomal somatic cell
hybrids to map the PKP1 gene to chromosome 1; fluorescence in situ
hybridization showed that the gene resides on the distal portion of 1q.
By fluorescence in situ hybridization and analysis of a somatic cell
hybrid mapping panel, Bonne et al. (1998) refined the mapping of the
PKP1 gene to 1q32.
MOLECULAR GENETICS
Members of the armadillo protein gene family, which includes plakoglobin
and beta-catenin (116806), have important functions in cytoskeleton/cell
membrane interactions. These proteins may act as linker molecules at
adherens junctions and desmosomes at the plasma membrane; in addition,
they may have pivotal roles in signal transduction pathways and
significant effects on cell behavior during development. McGrath et al.
(1997) described the first human mutations in 1 of these dual function
proteins. A 6-year-old boy with the ectodermal dysplasia/skin fragility
syndrome (604536) showed complete absence of immunostaining for
plakophilin-1 in the skin and was found to be a compound heterozygote
for 2 nonsense mutations of the PKP1 gene (601975.0001). Clinically,
there were features of both cutaneous fragility and congenital
ectodermal dysplasia affecting skin, hair, and nails. There was no
evidence of significant abnormalities in other epithelia or tissues.
Desmosomes in the skin were small and poorly formed with widening of
keratinocyte intercellular spaces and perturbed desmosome/keratin
intermediate filament interactions. The molecular findings and clinical
observations in this patient attested to the dual importance of
plakophilin-1 in both cutaneous cell-cell adhesion and epidermal
morphogenesis.
*FIELD* AV
.0001
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, GLN304TER
McGrath et al. (1997) found compound heterozygosity for 2 nonsense
mutations in the PKP1 gene in a 6-year-old boy with the ectodermal
dysplasia/skin fragility syndrome (604536). One allele of the PKF1 gene
carried a C-to-T transition that changed a glutamine residue (CAG) to a
stop codon (TAG). This mutation was present in the father also. The
other allele of the proband carried a 28-bp internal duplication
mutation (601975.0002), causing a frameshift and a stop codon 66 bp
downstream from the site of the insertion. This mutation was present in
the mother. The paternal mutation, gln304 to ter (Q304X), was present
within the first repeat domain, while the maternal duplication and
downstream premature termination codon resided within the third domain.
There was no family history of skin blistering or other significant
abnormalities and the parents were unrelated. At birth, the proband's
skin was lobster pink generally, with blistering on the soles. Over the
first 48 hours, he developed more severe blistering and desquamation on
the face, limbs, and buttocks. His hair was short and sparse, and the
nails were thickened and dystrophic. Subsequently, his skin continued to
show fragility, with trauma-induced tearing and blisters on the pressure
points of the soles after prolonged standing or walking.
.0002
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, 28-BP DUP, NT1132
See 601975.0001 and McGrath et al. (1997), who referred to this mutation
as 1132ins28.
.0003
ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
PKP1, IVS6, A-T, -2
Whittock et al. (2000) reported a homozygous splice site mutation
(1233-2 A-T) in a 17-year-old male with the ectodermal dysplasia/skin
fragility syndrome (604536). The clinical features comprised skin
erosions, dystrophic nails, sparse hair, and painful thickening and
cracking of palms and soles.
*FIELD* SA
Schmidt et al. (1997)
*FIELD* RF
1. Bonne, S.; van Hengel, J.; van Roy, F.: Chromosomal mapping of
human armadillo genes belonging to the p120(ctn)/plakophilin subfamily. Genomics 51:
452-454, 1998.
2. 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.
3. Hatzfeld, M.; Kristjansson, G. I.; Plessmann, U.; Weber, K.: Band
6 protein, a major constituent of desmosomes from stratified epithelia,
is a novel member of the armadillo multigene family. J. Cell Sci. 107:
2259-2270, 1994.
4. Heid, H. W.; Schmidt, A.; Zimbelmann, R.; Schafer, S.; Winter-Simanowski,
S.; Stumpp, S.; Keith, M.; Figge, U.; Schnolzer, M.; Franke, W. W.
: Cell type-specific desmosomal plaque proteins of the plakoglobin
family: plakophilin 1 (band 6 protein). Differentiation 58: 113-131,
1994.
5. McGrath, J. A.; McMillan, J. R.; Shemanko, C. S.; Runswick, S.
K.; Leigh, I. M.; Lane, E. B.; Garrod, D. R.; Eady, R. A. J.: Mutations
in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility
syndrome. Nature Genet. 17: 240-244, 1997.
6. McMillan, J. R.; Haftek, M.; Akiyama, M.; South, A. P.; Perrot,
H.; McGrath, J. A.; Eady, R. A. J.; Shimizu, H.: Alterations in desmosome
size and number coincide with the loss of keratinocyte cohesion in
skin with homozygous and heterozygous defects in the desmosomal protein
plakophilin 1. J. Invest Derm. 121: 96-103, 2003.
7. Schmidt, A.; Langbein, L.; Pratzel, S.; Rode, M.; Rackwitz, H.-R.;
Franke, W. W.: Plakophilin 3--a novel cell-type-specific desmosomal
plaque protein. Differentiation 64: 291-306, 1999.
8. Schmidt, A.; Langbein, L.; Rode, M.; Pratzel, S.; Zimbelmann, R.;
Franke, W. W.: Plakophilins 1a and 1b: widespread nuclear proteins
recruited in specific epithelial cells as desmosomal plaque components. Cell
Tissue Res. 290: 481-499, 1997.
9. Whittock, N. V.; Haftek, M.; Angoulvant, N.; Wolf, F.; Perrot,
H.; Eady, R. A. J.; McGrath, J. A.: Genomic amplification of the
human plakophilin 1 gene and detection of a new mutation in ectodermal
dysplasia/skin fragility syndrome. J. Invest. Derm. 115: 368-374,
2000.
*FIELD* CN
Gary A. Bellus - updated: 09/05/2003
Gary A. Bellus - updated: 4/6/2001
Carol A. Bocchini - updated: 1/18/2001
Sheryl A. Jankowski - updated: 11/2/1999
*FIELD* CD
Victor A. McKusick: 9/5/1997
*FIELD* ED
alopez: 09/05/2003
alopez: 9/5/2003
cwells: 4/25/2001
cwells: 4/12/2001
cwells: 4/6/2001
mcapotos: 3/15/2001
carol: 3/14/2001
carol: 1/18/2001
carol: 2/10/2000
psherman: 11/2/1999
terry: 7/29/1998
mark: 10/1/1997
dholmes: 9/30/1997
jenny: 9/30/1997
terry: 9/26/1997
jenny: 9/5/1997
MIM
604536
*RECORD*
*FIELD* NO
604536
*FIELD* TI
#604536 ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
;;MCGRATH SYNDROME
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
ectodermal dysplasia/skin fragility syndrome is caused by homozygous or
compound heterozygous mutation in the plakophilin-1 gene (PKP1; 601975)
on chromosome 1q32.
CLINICAL FEATURES
McGrath et al. (1997, 1999) described a boy with a unique skin disorder
comprising trauma-induced skin fragility and congenital ectodermal
dysplasia affecting hair, nails, and sweat glands. The proband reported
by McGrath et al. (1997) was a 6-year-old boy with unrelated parents.
There was no family history of skin blistering or other significant
abnormalities. At birth, all of his skin was lobster pink, with
blistering on the soles. Over the first 48 hours, he developed more
severe blistering and desquamation on his face, limbs, and buttocks. His
hair was noted to be short and sparse, and his nails were thickened and
dystrophic. Subsequently, his skin continued to show fragility, with
trauma-induced tearing and blisters on the pressure points of the soles
after prolonged standing or walking. Light microscopy of the skin
revealed thickening of the epidermis and extensive widening of
keratinocyte intercellular spaces, extending from the first suprabasal
layer upward. Electron microscopy showed a loss of
keratinocyte-keratinocyte adhesion, and desmosomes, particularly in the
lower suprabasal layers, were small and reduced in number. There was
complete absence of immunostaining for plakophilin-1 in the skin. The
proband was found to be a compound heterozygote for a premature
termination codon on each of the 2 alleles of the PKP1 gene (see
601975.0001 and 601975.0002).
McGrath (2000) reported observations on 2 further unrelated cases of
this syndrome. In one of these patients, a 17 year old, the scalp hair
started to regrow a little after the age of 7 years, and the abnormality
of sweating became much less marked. Most notable, however, was the
painful, disabling cracking and hyperkeratosis of the palms and soles,
also seen in the 3 other cases. The affected toddlers and children had
to be carried about by their parents, and the 17-year-old patient, who
had normal intelligence like the others, had gone through school in a
wheelchair due to the effects of the disease on the soles of the feet.
All 4 patients, who were from different families, showed loss of
plakophilin-1.
Using immunohistochemistry and quantitative electron microscopy,
McMillan et al. (2003) examined suprabasal desmosomes from 3
PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous
acceptor splice site mutation, and 5 healthy control subjects. Compared
with those in controls, desmosomes in PKP1-null patients were reduced
dramatically both in size (49%) and frequency (61%) in the lower
suprabasal layers (p less than 0.01). In the lower suprabasal
compartment of the heterozygous carrier, corresponding reductions were
37% and 20%, respectively (p less than 0.01). Surprisingly, in the
PKP1-null patients' upper suprabasal layer, desmosome size was larger
(59%, p less than 0.01) than the control value, and showed increased
desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal
layer desmosome frequency in PKP1-null patients was similar to that seen
in the lower suprabasal compartment but reduced by 43% compared to
controls. The carrier showed no difference in the upper suprabasal layer
desmosome size and frequency compared with the controls (p greater than
0.05). The PKP1-null patients showed poorly developed inner and outer
desmosomal plaques. Thus, both the patients and unaffected carrier
showed reductions in the lower suprabasal layer desmosome size and
number, despite only PKP1-null patients exhibiting any phenotype. These
findings attest to the molecular recruiting and stabilizing roles of
PKP1 in desmosome formation, particularly in the lower suprabasal
compartment.
MOLECULAR GENETICS
In a patient with ectodermal dysplasia/skin fragility syndrome, McGrath
et al. (1997) identified compound heterozygosity for premature
termination codons in the PKP1 gene (601975.0001-601975.0002).
In a 17-year-old patient with ectodermal dysplasia/skin fragility
syndrome, Whittock et al. (2000) identified a homozygous splice site
mutation in the PKP1 gene (601975.0003).
*FIELD* RF
1. McGrath, J. A.: Personal Communication. London, England 2/11/2000.
2. McGrath, J. A.; Hoeger, P. H.; Christiano, A. M.; McMillan, J.
R.; Mellerio, J. E.; Ashton, G. H. S.; Dopping-Hepenstal, P. J. C.;
Lake, B. D.; Leigh, I. M.; Harper, J. I.; Eady, R. A. J.: Skin fragility
and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin
1. Brit. J. Derm. 140: 297-307, 1999.
3. McGrath, J. A.; McMillan, J. R.; Shemanko, C. S.; Runswick, S.
K.; Leigh, I. M.; Lane, E. B.; Garrod, D. R.; Eady, R. A. J.: Mutations
in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility
syndrome. Nature Genet. 17: 240-244, 1997.
4. McMillan, J. R.; Haftek, M.; Akiyama, M.; South, A. P.; Perrot,
H.; McGrath, J. A.; Eady, R. A. J.; Shimizu, H.: Alterations in desmosome
size and number coincide with the loss of keratinocyte cohesion in
skin with homozygous and heterozygous defects in the desmosomal protein
plakophilin 1. J. Invest Derm. 121: 96-103, 2003.
5. Whittock, N. V.; Haftek, M.; Angoulvant, N.; Wolf, F.; Perrot,
H.; Eady, R. A. J.; McGrath, J. A.: Genomic amplification of the
human plakophilin 1 gene and detection of a new mutation in ectodermal
dysplasia/skin fragility syndrome. J. Invest. Derm. 115: 368-374,
2000.
*FIELD* CN
Gary A. Bellus - updated: 9/5/2003
Victor A. McKusick - updated: 2/25/2000
*FIELD* CD
Victor A. McKusick: 2/10/2000
*FIELD* ED
carol: 12/13/2011
alopez: 9/5/2003
terry: 10/4/2000
mcapotos: 8/8/2000
mgross: 3/15/2000
terry: 2/25/2000
carol: 2/10/2000
*RECORD*
*FIELD* NO
604536
*FIELD* TI
#604536 ECTODERMAL DYSPLASIA/SKIN FRAGILITY SYNDROME
;;MCGRATH SYNDROME
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
ectodermal dysplasia/skin fragility syndrome is caused by homozygous or
compound heterozygous mutation in the plakophilin-1 gene (PKP1; 601975)
on chromosome 1q32.
CLINICAL FEATURES
McGrath et al. (1997, 1999) described a boy with a unique skin disorder
comprising trauma-induced skin fragility and congenital ectodermal
dysplasia affecting hair, nails, and sweat glands. The proband reported
by McGrath et al. (1997) was a 6-year-old boy with unrelated parents.
There was no family history of skin blistering or other significant
abnormalities. At birth, all of his skin was lobster pink, with
blistering on the soles. Over the first 48 hours, he developed more
severe blistering and desquamation on his face, limbs, and buttocks. His
hair was noted to be short and sparse, and his nails were thickened and
dystrophic. Subsequently, his skin continued to show fragility, with
trauma-induced tearing and blisters on the pressure points of the soles
after prolonged standing or walking. Light microscopy of the skin
revealed thickening of the epidermis and extensive widening of
keratinocyte intercellular spaces, extending from the first suprabasal
layer upward. Electron microscopy showed a loss of
keratinocyte-keratinocyte adhesion, and desmosomes, particularly in the
lower suprabasal layers, were small and reduced in number. There was
complete absence of immunostaining for plakophilin-1 in the skin. The
proband was found to be a compound heterozygote for a premature
termination codon on each of the 2 alleles of the PKP1 gene (see
601975.0001 and 601975.0002).
McGrath (2000) reported observations on 2 further unrelated cases of
this syndrome. In one of these patients, a 17 year old, the scalp hair
started to regrow a little after the age of 7 years, and the abnormality
of sweating became much less marked. Most notable, however, was the
painful, disabling cracking and hyperkeratosis of the palms and soles,
also seen in the 3 other cases. The affected toddlers and children had
to be carried about by their parents, and the 17-year-old patient, who
had normal intelligence like the others, had gone through school in a
wheelchair due to the effects of the disease on the soles of the feet.
All 4 patients, who were from different families, showed loss of
plakophilin-1.
Using immunohistochemistry and quantitative electron microscopy,
McMillan et al. (2003) examined suprabasal desmosomes from 3
PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous
acceptor splice site mutation, and 5 healthy control subjects. Compared
with those in controls, desmosomes in PKP1-null patients were reduced
dramatically both in size (49%) and frequency (61%) in the lower
suprabasal layers (p less than 0.01). In the lower suprabasal
compartment of the heterozygous carrier, corresponding reductions were
37% and 20%, respectively (p less than 0.01). Surprisingly, in the
PKP1-null patients' upper suprabasal layer, desmosome size was larger
(59%, p less than 0.01) than the control value, and showed increased
desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal
layer desmosome frequency in PKP1-null patients was similar to that seen
in the lower suprabasal compartment but reduced by 43% compared to
controls. The carrier showed no difference in the upper suprabasal layer
desmosome size and frequency compared with the controls (p greater than
0.05). The PKP1-null patients showed poorly developed inner and outer
desmosomal plaques. Thus, both the patients and unaffected carrier
showed reductions in the lower suprabasal layer desmosome size and
number, despite only PKP1-null patients exhibiting any phenotype. These
findings attest to the molecular recruiting and stabilizing roles of
PKP1 in desmosome formation, particularly in the lower suprabasal
compartment.
MOLECULAR GENETICS
In a patient with ectodermal dysplasia/skin fragility syndrome, McGrath
et al. (1997) identified compound heterozygosity for premature
termination codons in the PKP1 gene (601975.0001-601975.0002).
In a 17-year-old patient with ectodermal dysplasia/skin fragility
syndrome, Whittock et al. (2000) identified a homozygous splice site
mutation in the PKP1 gene (601975.0003).
*FIELD* RF
1. McGrath, J. A.: Personal Communication. London, England 2/11/2000.
2. McGrath, J. A.; Hoeger, P. H.; Christiano, A. M.; McMillan, J.
R.; Mellerio, J. E.; Ashton, G. H. S.; Dopping-Hepenstal, P. J. C.;
Lake, B. D.; Leigh, I. M.; Harper, J. I.; Eady, R. A. J.: Skin fragility
and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin
1. Brit. J. Derm. 140: 297-307, 1999.
3. McGrath, J. A.; McMillan, J. R.; Shemanko, C. S.; Runswick, S.
K.; Leigh, I. M.; Lane, E. B.; Garrod, D. R.; Eady, R. A. J.: Mutations
in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility
syndrome. Nature Genet. 17: 240-244, 1997.
4. McMillan, J. R.; Haftek, M.; Akiyama, M.; South, A. P.; Perrot,
H.; McGrath, J. A.; Eady, R. A. J.; Shimizu, H.: Alterations in desmosome
size and number coincide with the loss of keratinocyte cohesion in
skin with homozygous and heterozygous defects in the desmosomal protein
plakophilin 1. J. Invest Derm. 121: 96-103, 2003.
5. Whittock, N. V.; Haftek, M.; Angoulvant, N.; Wolf, F.; Perrot,
H.; Eady, R. A. J.; McGrath, J. A.: Genomic amplification of the
human plakophilin 1 gene and detection of a new mutation in ectodermal
dysplasia/skin fragility syndrome. J. Invest. Derm. 115: 368-374,
2000.
*FIELD* CN
Gary A. Bellus - updated: 9/5/2003
Victor A. McKusick - updated: 2/25/2000
*FIELD* CD
Victor A. McKusick: 2/10/2000
*FIELD* ED
carol: 12/13/2011
alopez: 9/5/2003
terry: 10/4/2000
mcapotos: 8/8/2000
mgross: 3/15/2000
terry: 2/25/2000
carol: 2/10/2000