Full text data of DSG1
DSG1
(CDHF4)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Desmoglein-1 (Cadherin family member 4; Desmosomal glycoprotein 1; DG1; DGI; Pemphigus foliaceus antigen; Flags: Precursor)
Desmoglein-1 (Cadherin family member 4; Desmosomal glycoprotein 1; DG1; DGI; Pemphigus foliaceus antigen; Flags: Precursor)
UniProt
Q02413
ID DSG1_HUMAN Reviewed; 1049 AA.
AC Q02413;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-MAR-2010, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Desmoglein-1;
DE AltName: Full=Cadherin family member 4;
DE AltName: Full=Desmosomal glycoprotein 1;
DE Short=DG1;
DE Short=DGI;
DE AltName: Full=Pemphigus foliaceus antigen;
DE Flags: Precursor;
GN Name=DSG1; Synonyms=CDHF4;
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], AND VARIANT VAL-11.
RC TISSUE=Keratinocyte;
RX PubMed=1711210; DOI=10.1073/pnas.88.11.4796;
RA Wheeler G.N., Parker A.E., Thomas C.L., Ataliotis P., Poynter D.,
RA Arnemann J., Rutman A.J., Pidsley S.C., Watt F.M., Rees D.A.,
RA Buxton R.S., Magee A.I.;
RT "Desmosomal glycoprotein DGI, a component of intercellular desmosome
RT junctions, is related to the cadherin family of cell adhesion
RT molecules.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:4796-4800(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-11.
RC TISSUE=Foreskin;
RX PubMed=1770008;
RA Nilles L.A., Parry D.A., Powers E.E., Angst B.D., Wagner R.M.,
RA Green K.J.;
RT "Structural analysis and expression of human desmoglein: a cadherin-
RT like component of the desmosome.";
RL J. Cell Sci. 99:809-821(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D.,
RA Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S.,
RA Bloom T., Bugalter B., Butler J., Cook A., DeCaprio D., Engels R.,
RA Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T.,
RA Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E.,
RA Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H.,
RA O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [4]
RP INVOLVEMENT IN SPPK1.
RX PubMed=10332028; DOI=10.1093/hmg/8.6.971;
RA Rickman L., Simrak D., Stevens H.P., Hunt D.M., King I.A.,
RA Bryant S.P., Eady R.A.J., Leigh I.M., Arnemann J., Magee A.I.,
RA Kelsell D.P., Buxton R.S.;
RT "N-terminal deletion in a desmosomal cadherin causes the autosomal
RT dominant skin disease striate palmoplantar keratoderma.";
RL Hum. Mol. Genet. 8:971-976(1999).
RN [5]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-110, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [6]
RP INTERACTION WITH JUP/PLAKOGLOBIN.
RX PubMed=19759396; DOI=10.1074/jbc.M109.047928;
RA Choi H.J., Gross J.C., Pokutta S., Weis W.I.;
RT "Interactions of plakoglobin and beta-catenin with desmosomal
RT cadherins: basis of selective exclusion of alpha- and beta-catenin
RT from desmosomes.";
RL J. Biol. Chem. 284:31776-31788(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-579, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [8]
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).
CC -!- FUNCTION: Component of intercellular desmosome junctions. Involved
CC in the interaction of plaque proteins and intermediate filaments
CC mediating cell-cell adhesion.
CC -!- SUBUNIT: Binds to JUP/plakoglobin.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein (By similarity). Cell junction, desmosome.
CC -!- TISSUE SPECIFICITY: Epidermis, tongue, tonsil and esophagus.
CC -!- DOMAIN: Three calcium ions are usually bound at the interface of
CC each cadherin domain and rigidify the connections, imparting a
CC strong curvature to the full-length ectodomain (By similarity).
CC -!- DISEASE: Keratoderma, palmoplantar, striate 1 (SPPK1)
CC [MIM:148700]: A dermatological disorder characterized by
CC thickening of the skin on the palms and soles, and longitudinal
CC hyperkeratotic lesions on the palms, running the length of each
CC finger. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Contains 4 cadherin domains.
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; X56654; CAA39976.1; -; mRNA.
DR EMBL; AF097935; AAC83817.1; -; mRNA.
DR EMBL; AC009717; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; S16906; IJHUG1.
DR RefSeq; NP_001933.2; NM_001942.2.
DR UniGene; Hs.2633; -.
DR ProteinModelPortal; Q02413; -.
DR SMR; Q02413; 47-516.
DR IntAct; Q02413; 12.
DR STRING; 9606.ENSP00000257192; -.
DR PhosphoSite; Q02413; -.
DR DMDM; 292495005; -.
DR PaxDb; Q02413; -.
DR PRIDE; Q02413; -.
DR DNASU; 1828; -.
DR Ensembl; ENST00000257192; ENSP00000257192; ENSG00000134760.
DR GeneID; 1828; -.
DR KEGG; hsa:1828; -.
DR UCSC; uc002kwp.3; human.
DR CTD; 1828; -.
DR GeneCards; GC18P028921; -.
DR H-InvDB; HIX0039708; -.
DR HGNC; HGNC:3048; DSG1.
DR HPA; CAB009394; -.
DR HPA; HPA022128; -.
DR MIM; 125670; gene.
DR MIM; 148700; phenotype.
DR neXtProt; NX_Q02413; -.
DR Orphanet; 50942; Keratosis palmoplantaris striata.
DR PharmGKB; PA27501; -.
DR eggNOG; NOG283402; -.
DR HOGENOM; HOG000236266; -.
DR HOVERGEN; HBG005532; -.
DR InParanoid; Q02413; -.
DR KO; K07596; -.
DR OMA; EFRIQVR; -.
DR OrthoDB; EOG7VTDM9; -.
DR PhylomeDB; Q02413; -.
DR Reactome; REACT_578; Apoptosis.
DR GeneWiki; Desmoglein_1; -.
DR GenomeRNAi; 1828; -.
DR NextBio; 7461; -.
DR PMAP-CutDB; Q02413; -.
DR PRO; PR:Q02413; -.
DR ArrayExpress; Q02413; -.
DR Bgee; Q02413; -.
DR CleanEx; HS_DSG1; -.
DR Genevestigator; Q02413; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030057; C:desmosome; NAS:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0016328; C:lateral plasma membrane; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; NAS:UniProtKB.
DR GO; GO:0015643; F:toxic substance binding; NAS:UniProtKB.
DR GO; GO:0016339; P:calcium-dependent cell-cell adhesion; NAS:UniProtKB.
DR GO; GO:0007043; P:cell-cell junction assembly; NAS:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0007156; P:homophilic cell adhesion; IEA:InterPro.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IDA:BHF-UCL.
DR GO; GO:0032570; P:response to progesterone stimulus; IEA:Ensembl.
DR Gene3D; 2.60.40.60; -; 4.
DR Gene3D; 4.10.900.10; -; 1.
DR InterPro; IPR002126; Cadherin.
DR InterPro; IPR015919; Cadherin-like.
DR InterPro; IPR020894; Cadherin_CS.
DR InterPro; IPR000233; Cadherin_cytoplasmic-dom.
DR InterPro; IPR027397; Catenin_binding_dom.
DR InterPro; IPR009123; Desmoglein.
DR InterPro; IPR009122; Desmosomal_cadherin.
DR PANTHER; PTHR24025; PTHR24025; 1.
DR Pfam; PF00028; Cadherin; 3.
DR Pfam; PF01049; Cadherin_C; 1.
DR PRINTS; PR00205; CADHERIN.
DR PRINTS; PR01818; DESMOCADHERN.
DR PRINTS; PR01819; DESMOGLEIN.
DR SMART; SM00112; CA; 4.
DR SUPFAM; SSF49313; SSF49313; 4.
DR PROSITE; PS00232; CADHERIN_1; 2.
DR PROSITE; PS50268; CADHERIN_2; 4.
PE 1: Evidence at protein level;
KW Calcium; Cell adhesion; Cell junction; Cell membrane;
KW Cleavage on pair of basic residues; Complete proteome; Glycoprotein;
KW Membrane; Metal-binding; Palmoplantar keratoderma; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 23 Potential.
FT PROPEP 24 49 Potential.
FT /FTId=PRO_0000003837.
FT CHAIN 50 1049 Desmoglein-1.
FT /FTId=PRO_0000003838.
FT TOPO_DOM 50 548 Extracellular (Potential).
FT TRANSMEM 549 569 Helical; (Potential).
FT TOPO_DOM 570 1049 Cytoplasmic (Potential).
FT DOMAIN 50 158 Cadherin 1.
FT DOMAIN 159 270 Cadherin 2.
FT DOMAIN 271 385 Cadherin 3.
FT DOMAIN 386 497 Cadherin 4.
FT REPEAT 813 839 Desmoglein repeat 1.
FT REPEAT 840 869 Desmoglein repeat 2.
FT REPEAT 870 899 Desmoglein repeat 3.
FT REPEAT 900 927 Desmoglein repeat 4.
FT REPEAT 928 956 Desmoglein repeat 5.
FT COMPBIAS 969 1019 Gly/Ser-rich.
FT MOD_RES 579 579 Phosphoserine.
FT CARBOHYD 36 36 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 110 110 N-linked (GlcNAc...).
FT CARBOHYD 180 180 N-linked (GlcNAc...) (Potential).
FT VARIANT 11 11 M -> V (in dbSNP:rs1426310).
FT /FTId=VAR_060248.
FT VARIANT 395 395 T -> S (in dbSNP:rs16961655).
FT /FTId=VAR_055573.
FT VARIANT 493 493 N -> T (in dbSNP:rs8091003).
FT /FTId=VAR_024385.
FT VARIANT 498 498 T -> N (in dbSNP:rs8091117).
FT /FTId=VAR_024386.
FT VARIANT 528 528 Y -> S (in dbSNP:rs16961689).
FT /FTId=VAR_055574.
FT VARIANT 538 538 D -> N (in dbSNP:rs34302455).
FT /FTId=VAR_055575.
FT VARIANT 665 665 M -> I (in dbSNP:rs35360042).
FT /FTId=VAR_055576.
FT VARIANT 821 821 L -> Q (in dbSNP:rs16961692).
FT /FTId=VAR_055577.
FT VARIANT 828 828 D -> N (in dbSNP:rs3752094).
FT /FTId=VAR_060249.
FT VARIANT 841 841 Y -> F (in dbSNP:rs3752095).
FT /FTId=VAR_020364.
SQ SEQUENCE 1049 AA; 113748 MW; FEA471244B9D67AE CRC64;
MDWSFFRVVA MLFIFLVVVE VNSEFRIQVR DYNTKNGTIK WHSIRRQKRE WIKFAAACRE
GEDNSKRNPI AKIHSDCAAN QQVTYRISGV GIDQPPYGIF VINQKTGEIN ITSIVDREVT
PFFIIYCRAL NSMGQDLERP LELRVRVLDI NDNPPVFSMA TFAGQIEENS NANTLVMILN
ATDADEPNNL NSKIAFKIIR QEPSDSPMFI INRNTGEIRT MNNFLDREQY GQYALAVRGS
DRDGGADGMS AECECNIKIL DVNDNIPYME QSSYTIEIQE NTLNSNLLEI RVIDLDEEFS
ANWMAVIFFI SGNEGNWFEI EMNERTNVGI LKVVKPLDYE AMQSLQLSIG VRNKAEFHHS
IMSQYKLKAS AISVTVLNVI EGPVFRPGSK TYVVTGNMGS NDKVGDFVAT DLDTGRPSTT
VRYVMGNNPA DLLAVDSRTG KLTLKNKVTK EQYNMLGGKY QGTILSIDDN LQRTCTGTIN
INIQSFGNDD RTNTEPNTKI TTNTGRQEST SSTNYDTSTT STDSSQVYSS EPGNGAKDLL
SDNVHFGPAG IGLLIMGFLV LGLVPFLMIC CDCGGAPRSA AGFEPVPECS DGAIHSWAVE
GPQPEPRDIT TVIPQIPPDN ANIIECIDNS GVYTNEYGGR EMQDLGGGER MTGFELTEGV
KTSGMPEICQ EYSGTLRRNS MRECREGGLN MNFMESYFCQ KAYAYADEDE GRPSNDCLLI
YDIEGVGSPA GSVGCCSFIG EDLDDSFLDT LGPKFKKLAD ISLGKESYPD LDPSWPPQST
EPVCLPQETE PVVSGHPPIS PHFGTTTVIS ESTYPSGPGV LHPKPILDPL GYGNVTVTES
YTTSDTLKPS VHVHDNRPAS NVVVTERVVG PISGADLHGM LEMPDLRDGS NVIVTERVIA
PSSSLPTSLT IHHPRESSNV VVTERVIQPT SGMIGSLSMH PELANAHNVI VTERVVSGAG
VTGISGTTGI SGGIGSSGLV GTSMGAGSGA LSGAGISGGG IGLSSLGGTA SIGHMRSSSD
HHFNQTIGSA SPSTARSRIT KYSTVQYSK
//
ID DSG1_HUMAN Reviewed; 1049 AA.
AC Q02413;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-MAR-2010, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Desmoglein-1;
DE AltName: Full=Cadherin family member 4;
DE AltName: Full=Desmosomal glycoprotein 1;
DE Short=DG1;
DE Short=DGI;
DE AltName: Full=Pemphigus foliaceus antigen;
DE Flags: Precursor;
GN Name=DSG1; Synonyms=CDHF4;
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], AND VARIANT VAL-11.
RC TISSUE=Keratinocyte;
RX PubMed=1711210; DOI=10.1073/pnas.88.11.4796;
RA Wheeler G.N., Parker A.E., Thomas C.L., Ataliotis P., Poynter D.,
RA Arnemann J., Rutman A.J., Pidsley S.C., Watt F.M., Rees D.A.,
RA Buxton R.S., Magee A.I.;
RT "Desmosomal glycoprotein DGI, a component of intercellular desmosome
RT junctions, is related to the cadherin family of cell adhesion
RT molecules.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:4796-4800(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-11.
RC TISSUE=Foreskin;
RX PubMed=1770008;
RA Nilles L.A., Parry D.A., Powers E.E., Angst B.D., Wagner R.M.,
RA Green K.J.;
RT "Structural analysis and expression of human desmoglein: a cadherin-
RT like component of the desmosome.";
RL J. Cell Sci. 99:809-821(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D.,
RA Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S.,
RA Bloom T., Bugalter B., Butler J., Cook A., DeCaprio D., Engels R.,
RA Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T.,
RA Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E.,
RA Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H.,
RA O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [4]
RP INVOLVEMENT IN SPPK1.
RX PubMed=10332028; DOI=10.1093/hmg/8.6.971;
RA Rickman L., Simrak D., Stevens H.P., Hunt D.M., King I.A.,
RA Bryant S.P., Eady R.A.J., Leigh I.M., Arnemann J., Magee A.I.,
RA Kelsell D.P., Buxton R.S.;
RT "N-terminal deletion in a desmosomal cadherin causes the autosomal
RT dominant skin disease striate palmoplantar keratoderma.";
RL Hum. Mol. Genet. 8:971-976(1999).
RN [5]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-110, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [6]
RP INTERACTION WITH JUP/PLAKOGLOBIN.
RX PubMed=19759396; DOI=10.1074/jbc.M109.047928;
RA Choi H.J., Gross J.C., Pokutta S., Weis W.I.;
RT "Interactions of plakoglobin and beta-catenin with desmosomal
RT cadherins: basis of selective exclusion of alpha- and beta-catenin
RT from desmosomes.";
RL J. Biol. Chem. 284:31776-31788(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-579, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [8]
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).
CC -!- FUNCTION: Component of intercellular desmosome junctions. Involved
CC in the interaction of plaque proteins and intermediate filaments
CC mediating cell-cell adhesion.
CC -!- SUBUNIT: Binds to JUP/plakoglobin.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein (By similarity). Cell junction, desmosome.
CC -!- TISSUE SPECIFICITY: Epidermis, tongue, tonsil and esophagus.
CC -!- DOMAIN: Three calcium ions are usually bound at the interface of
CC each cadherin domain and rigidify the connections, imparting a
CC strong curvature to the full-length ectodomain (By similarity).
CC -!- DISEASE: Keratoderma, palmoplantar, striate 1 (SPPK1)
CC [MIM:148700]: A dermatological disorder characterized by
CC thickening of the skin on the palms and soles, and longitudinal
CC hyperkeratotic lesions on the palms, running the length of each
CC finger. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Contains 4 cadherin domains.
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; X56654; CAA39976.1; -; mRNA.
DR EMBL; AF097935; AAC83817.1; -; mRNA.
DR EMBL; AC009717; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; S16906; IJHUG1.
DR RefSeq; NP_001933.2; NM_001942.2.
DR UniGene; Hs.2633; -.
DR ProteinModelPortal; Q02413; -.
DR SMR; Q02413; 47-516.
DR IntAct; Q02413; 12.
DR STRING; 9606.ENSP00000257192; -.
DR PhosphoSite; Q02413; -.
DR DMDM; 292495005; -.
DR PaxDb; Q02413; -.
DR PRIDE; Q02413; -.
DR DNASU; 1828; -.
DR Ensembl; ENST00000257192; ENSP00000257192; ENSG00000134760.
DR GeneID; 1828; -.
DR KEGG; hsa:1828; -.
DR UCSC; uc002kwp.3; human.
DR CTD; 1828; -.
DR GeneCards; GC18P028921; -.
DR H-InvDB; HIX0039708; -.
DR HGNC; HGNC:3048; DSG1.
DR HPA; CAB009394; -.
DR HPA; HPA022128; -.
DR MIM; 125670; gene.
DR MIM; 148700; phenotype.
DR neXtProt; NX_Q02413; -.
DR Orphanet; 50942; Keratosis palmoplantaris striata.
DR PharmGKB; PA27501; -.
DR eggNOG; NOG283402; -.
DR HOGENOM; HOG000236266; -.
DR HOVERGEN; HBG005532; -.
DR InParanoid; Q02413; -.
DR KO; K07596; -.
DR OMA; EFRIQVR; -.
DR OrthoDB; EOG7VTDM9; -.
DR PhylomeDB; Q02413; -.
DR Reactome; REACT_578; Apoptosis.
DR GeneWiki; Desmoglein_1; -.
DR GenomeRNAi; 1828; -.
DR NextBio; 7461; -.
DR PMAP-CutDB; Q02413; -.
DR PRO; PR:Q02413; -.
DR ArrayExpress; Q02413; -.
DR Bgee; Q02413; -.
DR CleanEx; HS_DSG1; -.
DR Genevestigator; Q02413; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030057; C:desmosome; NAS:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0016328; C:lateral plasma membrane; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; NAS:UniProtKB.
DR GO; GO:0015643; F:toxic substance binding; NAS:UniProtKB.
DR GO; GO:0016339; P:calcium-dependent cell-cell adhesion; NAS:UniProtKB.
DR GO; GO:0007043; P:cell-cell junction assembly; NAS:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0007156; P:homophilic cell adhesion; IEA:InterPro.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IDA:BHF-UCL.
DR GO; GO:0032570; P:response to progesterone stimulus; IEA:Ensembl.
DR Gene3D; 2.60.40.60; -; 4.
DR Gene3D; 4.10.900.10; -; 1.
DR InterPro; IPR002126; Cadherin.
DR InterPro; IPR015919; Cadherin-like.
DR InterPro; IPR020894; Cadherin_CS.
DR InterPro; IPR000233; Cadherin_cytoplasmic-dom.
DR InterPro; IPR027397; Catenin_binding_dom.
DR InterPro; IPR009123; Desmoglein.
DR InterPro; IPR009122; Desmosomal_cadherin.
DR PANTHER; PTHR24025; PTHR24025; 1.
DR Pfam; PF00028; Cadherin; 3.
DR Pfam; PF01049; Cadherin_C; 1.
DR PRINTS; PR00205; CADHERIN.
DR PRINTS; PR01818; DESMOCADHERN.
DR PRINTS; PR01819; DESMOGLEIN.
DR SMART; SM00112; CA; 4.
DR SUPFAM; SSF49313; SSF49313; 4.
DR PROSITE; PS00232; CADHERIN_1; 2.
DR PROSITE; PS50268; CADHERIN_2; 4.
PE 1: Evidence at protein level;
KW Calcium; Cell adhesion; Cell junction; Cell membrane;
KW Cleavage on pair of basic residues; Complete proteome; Glycoprotein;
KW Membrane; Metal-binding; Palmoplantar keratoderma; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 23 Potential.
FT PROPEP 24 49 Potential.
FT /FTId=PRO_0000003837.
FT CHAIN 50 1049 Desmoglein-1.
FT /FTId=PRO_0000003838.
FT TOPO_DOM 50 548 Extracellular (Potential).
FT TRANSMEM 549 569 Helical; (Potential).
FT TOPO_DOM 570 1049 Cytoplasmic (Potential).
FT DOMAIN 50 158 Cadherin 1.
FT DOMAIN 159 270 Cadherin 2.
FT DOMAIN 271 385 Cadherin 3.
FT DOMAIN 386 497 Cadherin 4.
FT REPEAT 813 839 Desmoglein repeat 1.
FT REPEAT 840 869 Desmoglein repeat 2.
FT REPEAT 870 899 Desmoglein repeat 3.
FT REPEAT 900 927 Desmoglein repeat 4.
FT REPEAT 928 956 Desmoglein repeat 5.
FT COMPBIAS 969 1019 Gly/Ser-rich.
FT MOD_RES 579 579 Phosphoserine.
FT CARBOHYD 36 36 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 110 110 N-linked (GlcNAc...).
FT CARBOHYD 180 180 N-linked (GlcNAc...) (Potential).
FT VARIANT 11 11 M -> V (in dbSNP:rs1426310).
FT /FTId=VAR_060248.
FT VARIANT 395 395 T -> S (in dbSNP:rs16961655).
FT /FTId=VAR_055573.
FT VARIANT 493 493 N -> T (in dbSNP:rs8091003).
FT /FTId=VAR_024385.
FT VARIANT 498 498 T -> N (in dbSNP:rs8091117).
FT /FTId=VAR_024386.
FT VARIANT 528 528 Y -> S (in dbSNP:rs16961689).
FT /FTId=VAR_055574.
FT VARIANT 538 538 D -> N (in dbSNP:rs34302455).
FT /FTId=VAR_055575.
FT VARIANT 665 665 M -> I (in dbSNP:rs35360042).
FT /FTId=VAR_055576.
FT VARIANT 821 821 L -> Q (in dbSNP:rs16961692).
FT /FTId=VAR_055577.
FT VARIANT 828 828 D -> N (in dbSNP:rs3752094).
FT /FTId=VAR_060249.
FT VARIANT 841 841 Y -> F (in dbSNP:rs3752095).
FT /FTId=VAR_020364.
SQ SEQUENCE 1049 AA; 113748 MW; FEA471244B9D67AE CRC64;
MDWSFFRVVA MLFIFLVVVE VNSEFRIQVR DYNTKNGTIK WHSIRRQKRE WIKFAAACRE
GEDNSKRNPI AKIHSDCAAN QQVTYRISGV GIDQPPYGIF VINQKTGEIN ITSIVDREVT
PFFIIYCRAL NSMGQDLERP LELRVRVLDI NDNPPVFSMA TFAGQIEENS NANTLVMILN
ATDADEPNNL NSKIAFKIIR QEPSDSPMFI INRNTGEIRT MNNFLDREQY GQYALAVRGS
DRDGGADGMS AECECNIKIL DVNDNIPYME QSSYTIEIQE NTLNSNLLEI RVIDLDEEFS
ANWMAVIFFI SGNEGNWFEI EMNERTNVGI LKVVKPLDYE AMQSLQLSIG VRNKAEFHHS
IMSQYKLKAS AISVTVLNVI EGPVFRPGSK TYVVTGNMGS NDKVGDFVAT DLDTGRPSTT
VRYVMGNNPA DLLAVDSRTG KLTLKNKVTK EQYNMLGGKY QGTILSIDDN LQRTCTGTIN
INIQSFGNDD RTNTEPNTKI TTNTGRQEST SSTNYDTSTT STDSSQVYSS EPGNGAKDLL
SDNVHFGPAG IGLLIMGFLV LGLVPFLMIC CDCGGAPRSA AGFEPVPECS DGAIHSWAVE
GPQPEPRDIT TVIPQIPPDN ANIIECIDNS GVYTNEYGGR EMQDLGGGER MTGFELTEGV
KTSGMPEICQ EYSGTLRRNS MRECREGGLN MNFMESYFCQ KAYAYADEDE GRPSNDCLLI
YDIEGVGSPA GSVGCCSFIG EDLDDSFLDT LGPKFKKLAD ISLGKESYPD LDPSWPPQST
EPVCLPQETE PVVSGHPPIS PHFGTTTVIS ESTYPSGPGV LHPKPILDPL GYGNVTVTES
YTTSDTLKPS VHVHDNRPAS NVVVTERVVG PISGADLHGM LEMPDLRDGS NVIVTERVIA
PSSSLPTSLT IHHPRESSNV VVTERVIQPT SGMIGSLSMH PELANAHNVI VTERVVSGAG
VTGISGTTGI SGGIGSSGLV GTSMGAGSGA LSGAGISGGG IGLSSLGGTA SIGHMRSSSD
HHFNQTIGSA SPSTARSRIT KYSTVQYSK
//
MIM
125670
*RECORD*
*FIELD* NO
125670
*FIELD* TI
*125670 DESMOGLEIN 1; DSG1
;;PEMPHIGUS FOLIACEUS ANTIGEN; PFA
*FIELD* TX
DESCRIPTION
read more
The calcium-binding transmembrane glycoproteins DG I (desmoglein; M(r)
150,000) and the related proteins DG II and DG III (desmocollins; see
DSC2, 125645) comprise the major proteins of the urea-insoluble core of
the desmosome. Desmosomes are the most common type of intercellular
junction in vertebrate epithelial cells. Desmosomal proteins can be
divided into 2 groups on the basis of whether they fractionate with the
core or the urea-soluble 'plaque' components (summary by Arnemann et
al., 1991).
GENE STRUCTURE
Hunt et al. (2001) presented the complete exon-intron structure of the
DSG1 gene, which contains 15 exons and spans about 43 kb.
MAPPING
Arnemann et al. (1991) designed a PCR assay for the gene coding for
desmoglein and used it to test human/mouse and human/rat somatic cell
hybrids with different contents of human chromosomes. In this way, they
were able to assign DSG to chromosome 18.
By fluorescence in situ hybridization, Wang et al. (1994) mapped both
the DSG1 gene and the DSG3 gene to 18q12. Furthermore, both of the genes
were localized on a 320-kb genomic fragment separated by pulsed field
gel electrophoresis.
Buxton et al. (1994) demonstrated that the murine homologs of DSC2 and
DSG1 are closely linked in the proximal region of mouse chromosome 18.
From a study of YAC clones, Simrak et al. (1995) found that the DSG1,
DSG2 (125671), and DSG3 genes are clustered within a region of less than
150 kb in 18q12.1. From restriction enzyme analysis, they showed that
the order of the DSG genes and their orientation is as follows:
5-prime--DSG1--DSG3--DSG2--3-prime. The desmoglein isoforms are
expressed in a stratification-related manner in human epidermis, DSG1
being suprabasally expressed and DSG3 at a lower level, while DSG2
expression is weak and basal. Thus there appears to be some
correspondence between the order of the DSG genes on chromosome 18 and
their expression within tissues, raising the possibility that the
organization of the cluster is required for properly regulated gene
expression.
GENE FUNCTION
Amagai et al. (1991) demonstrated that desmoglein-1 is the antigen
target in the autoimmune disease of skin, pemphigus foliaceus; DSG3
(169615) is the antigen target in pemphigus vulgaris.
Pemphigus foliaceus is an autoimmune skin disease mediated by
autoantibodies against desmoglein-1. The endemic form, known as fogo
selvagem, is thought to have an environmental cause. Warren et al.
(2000) performed an epidemiologic study including an area of Brazil,
Limao Verde, with a prevalence of 3.4% of fogo selvagem in the
population. In 59 of 60 patients with the disorder, antibodies against
desmoglein-1 were detected, whereas such antibodies were found in only 3
of 126 normal subjects from the United States and Japan. Antibodies were
also detected in 51 of 93 normal subjects from Limao Verde, and in 54 of
279 normal subjects from surrounding areas. Serum samples obtained 1 to
4 years before the onset of the disease were available for 5 patients;
all 5 had antibodies in the initial serum samples, and the onset of
disease was associated with a marked increase in antibody values. Warren
et al. (2000) concluded that there must be an unknown environmental
agent that initiates production of antibodies against desmoglein-1.
In pregnant women with pemphigus foliaceus, autoantibodies cross the
placenta and bind to the fetal epidermis, but they rarely cause blisters
in neonates. Wu et al. (2000) hypothesized that the coexpression of
desmoglein-3 in the superficial epidermis in neonates (but not in
adults) protects their skin from blistering caused by passively
transferred maternal antibodies against desmoglein-1, with the presence
of desmoglein-3 compensating for the antibody-induced loss of
desmoglein-1. They presented evidence supporting this hypothesis in the
form of observations in human neonatal and adult skin and in transgenic
mice. Transgenic mice expressed desmoglein-3 in both the superficial and
deep layers of the epidermis.
MOLECULAR GENETICS
- Palmoplantar Keratoderma
The N-terminal extracellular domain of the cadherins, calcium-dependent
cell adhesion molecules, has been shown by x-ray crystallography to be
involved in 2 types of interactions: lateral strand dimers and adhesive
dimers. Rickman et al. (1999) described the first mutation in a cadherin
present in desmosome cell junctions that removes a portion of this
highly conserved first extracellular domain (125670.0001). This
mutation, in the DSG1 gene coding for desmoglein-1, resulted in the
deletion of the first and much of the second beta-strand of the first
cadherin repeat and part of the first Ca(2+)-binding site, and would be
expected to compromise strand dimer formation.
The heterozygous mutation identified by Rickman et al. (1999)
(IVS3-1G-A; 125670.0001) occurred in a 3-generation Dutch family with
striate palmoplantar keratoderma type I (PPKS1; 148700) and segregated
with the disease. The mutation caused aberrant splicing of exon 2 to
exon 4, which are in-frame, with the consequent removal of exon 3
encoding part of the prosequence, the mature protein cleavage site, and
part of the first extracellular domain. This mutation emphasized the
importance of this part of the molecule for cadherin function, and of
the DSG1 protein and hence desmosomes in epidermal function. In the
Dutch pedigree, affected individuals were present in 2 generations with
male-to-male transmission. By inference, one member of an earlier
generation was affected but was not clinically diagnosed. Rickman et al.
(1999) concluded that haploinsufficiency was probably a mechanism of the
dominant disorder in the family. The rather mild clinical symptoms could
have been a consequence of the partial efficiency of missplicing and the
fact that affected individuals were heterozygotes, so that only a
fraction of DSG1 was of the abnormal type lacking exon 3.
Hunt et al. (2001) performed sequence analysis in 5 unrelated cases of
keratosis palmoplantaris striata I and identified heterozygous mutations
(in exons 2, 9, and 11) involving extracellular domains of the DSG1
protein (see, e.g., 125670.0002-125670.0004). All the mutations caused
truncated proteins due to nonsense mutations or to deletions or
insertions resulting in frameshifts, and haploinsufficiency was the most
probable mechanism of the dominant inheritance of the disorder.
In a family of Jewish Yemenite origin with autosomal dominant diffuse
PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and
identified a heterozygous nonsense mutation (R26X; 125670.0004) that
segregated completely with the disease. The same mutation had previously
been detected in a sporadic patient with striate PPK (Hunt et al.,
2001).
In a father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma from a consanguineous Libyan family, Milingou
et al. (2006) identified heterozygosity for a frameshift mutation in the
DSG1 gene (125670.0005) that was not found in unaffected family members
or in 50 unrelated controls. The authors noted that the phenotype in
this family extended the spectrum of clinical features associated with
genetic defects in DSG1.
Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with
PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi
origin, and identified 3 different heterozygous truncating mutations
(see, e.g., 125670.0006) that segregated with disease in each family,
respectively. Direct sequencing of cDNA derived from affected skin
failed to reveal a pathogenic mutation, suggesting that PPKS results
from haploinsufficiency for DSG1.
Dua-Awereh et al. (2009) sequenced the DSG1 gene in 5 Pakistani families
segregating autosomal dominant PPKS and identified distinct heterozygous
mutations in each family, including the recurrent R26X mutation
(125670.0004). Consistent with previous reports, all 5 mutations were
predicted to result in premature termination codons.
- Congenital Erythroderma with Palmoplantar Keratoderma, Hypotrichosis,
and Hyper-IgE
In affected members of 2 unrelated consanguineous families with
congenital erythroderma with palmoplantar keratoderma, hypotrichosis,
and hyper-IgE (EPKHE; 615508), Samuelov et al. (2013) identified 2
different homozygous mutations in the DSG1 gene (125670.0008 and
125670.0009). The mutations segregated with disease in each family, and
all heterozygous carriers displayed palmoplantar hyperkeratotic papules
and plaques, primarily in a nonstriated pattern. Functional analysis
showed that both mutations resulted in loss of expression of DSG1 at the
cell membrane.
*FIELD* AV
.0001
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, IVS2AS, G-A, -1
In a 3-generation Dutch family with striate palmoplantar keratoderma
mapping to chromosome 18 (PPKS1; 148700), Rickman et al. (1999) found a
G-to-A transition in the 3-prime splice acceptor site of intron 1 of the
DSG1 gene that segregated with the disease phenotype. This resulted in
an in-frame deletion of exon 3 encoding part of the prosequence, the
mature protein cleavage site, and part of the highly conserved first
extracellular domain. Affected individuals were present over 2
generations in the Dutch kindred, with male-to-male transmission, and by
inference, one member of an earlier generation was affected but was not
clinically diagnosed. Rickman et al. (1999) concluded that
haploinsufficiency was probably a mechanism of the dominant disorder in
this family, and suggested that their rather mild clinical symptoms
might have been a consequence of the partial efficiency of missplicing
and the fact that affected individuals were heterozygotes, so that only
a fraction of DSG1 was of the abnormal type lacking exon 3.
.0002
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, 1-BP INS, 1079C
In an affected member of a German kindred with striate palmoplantar
keratoderma (PPKS1; 148700), originally studied by Hennies et al.
(1995), Hunt et al. (2001) identified heterozygosity for a 1-bp
insertion (c.1079insC) in exon 9 of the DSG1 gene, causing a frameshift
predicted to result in a premature termination codon 6 residues
downstream. The mutation was not found in 50 unrelated ethnically
matched controls.
.0003
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, 1-BP DEL, 1627A
In a proband with striate palmoplantar keratoderma (PPKS1; 148700), Hunt
et al. (2001) identified heterozygosity for a 1-bp deletion (c.1627delA)
in exon 11 of the DSG1 gene, causing a frameshift predicted to result in
a premature termination codon 18 residues downstream. The mutation was
not found in 50 unrelated ethnically matched controls.
.0004
PALMOPLANTAR KERATODERMA I, STRIATE OR DIFFUSE
DSG1, ARG26TER
In a sporadic patient with striate palmoplantar keratoderma (PPKS1;
148700), Hunt et al. (2001) identified heterozygosity for a c.76C-T
transition in exon 2 of the DSG1 gene, resulting in an arg26-to-ter
(R26X) substitution.
In a father and 3 daughters from a family of Jewish Yemenite origin with
diffuse nonstriated palmoplantar keratoderma (see 148700), Keren et al.
(2005) identified heterozygosity for the DSG1 R26X mutation. The
mutation segregated completely with disease in the family. The 3
affected daughters exhibited a milder form of keratoderma than their
father, with lesions primarily on the soles.
In 6 affected members over 3 generations of a Pakistani family with
PPKS, Dua-Awereh et al. (2009) identified heterozygosity for the R26X
mutation in the DSG1 gene.
.0005
PALMOPLANTAR KERATODERMA I, FOCAL
DSG1, 1-BP INS, 121T
In a Libyan father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma (see 148700), Milingou et al. (2006) identified
heterozygosity for a 1-bp insertion (c.121insT) in exon 3 of the DSG1
gene, causing a frameshift predicted to result in a premature
termination codon 10 residues downstream. The mutation was not found in
unaffected family members or in 50 unrelated controls.
.0006
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, GLN201TER
In 5 affected members over 3 generations of a family with striate
palmoplantar keratoderma (PPKS1; 148700) of Jewish Sephardic descent,
Hershkovitz et al. (2008) identified heterozygosity for a c.602C-T
transition in the DSG1 gene, resulting in a gln201-to-ter (Q201X)
substitution in the second extracellular domain. The mutation was not
found in 9 unaffected family members or in 50 population-matched healthy
controls. RT-PCR of a biopsy from affected skin revealed loss of the
mutant transcript, suggesting that PPKS1 occurs as a result of
haploinsufficiency due to nonsense-mediated decay.
.0007
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, ARG144TER
In a 40-year-old Scottish man with striate palmoplantar keratoderma
(PPKS1; 148700), Zamiri et al. (2009) identified heterozygosity for a
c.430A-T transversion in exon 5 of the DSG1 gene, resulting in an
arg144-to-ter (R144X) substitution. The mutation was present in his
affected daughter but not his unaffected son. Immunohistochemistry of
affected plantar epidermis from the proband showed prominent staining of
DSG1 in the suprabasal, spinous, and lower granular layers.
.0008
ERYTHRODERMA, CONGENITAL, WITH PALMOPLANTAR KERATODERMA, HYPOTRICHOSIS,
AND HYPER-IgE
DSG1, IVS1, G-A, -1
In 2 sisters from a consanguineous Arab Muslim family with congenital
erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE
(EPKHE; 615508), Samuelov et al. (2013) identified homozygosity for a
c.49-1G-A transition in intron 1 of the DSG1 gene. Direct sequencing of
patient cDNA demonstrated skipping of exon 2, which was predicted to
disrupt the DSG1 signal peptide. The parents, who were both heterozygous
for the mutation, displayed palmoplantar hyperkeratosis. Patient
keratinocytes showed DSG1 accumulation in the cytoplasm, particularly
around the nucleus, in contrast to control keratinocytes, which showed
continuous membrane staining for DSG1. Immunostaining also demonstrated
cytoplasmic mislocalization of DSG1 in patient keratinocytes compared to
control biopsies, and double staining for markers of endoplasmic
reticulum, Golgi, and endosome showed partial colocalization of
cytoplasmic DSG1 with these endomembrane compartments in patient cells.
.0009
ERYTHRODERMA, CONGENITAL, WITH PALMOPLANTAR KERATODERMA, HYPOTRICHOSIS,
AND HYPER-IgE
DSG1, 1-BP DEL, 1861G
In affected members of a consanguineous family of Druze descent with
congenital erythroderma with palmoplantar keratoderma, hypotrichosis,
and hyper-IgE (EPKHE; 615508), Samuelov et al. (2013) identified
homozygosity for a 1-bp deletion (c.1861delG) in the DSG1 gene, causing
a frameshift predicted to result in a premature termination codon
(Ala621GlnfsTer3). Patient skin biopsy showed almost absent DSG1 mRNA,
likely reflecting mRNA decay; consistent with this observation,
immunofluorescent staining for DSG1 was also largely negative. All
heterozygous carriers of the deletion exhibited palmoplantar
hyperkeratosis.
*FIELD* RF
1. Amagai, M.; Klaus-Kovtun, V.; Stanley, J. R.: Autoantibodies against
a novel epithelial cadherin in pemphigus vulgaris, a disease of cell
adhesion. Cell 67: 869-877, 1991.
2. Arnemann, J.; Spurr, N. K.; Wheeler, G. N.; Parker, A. E.; Buxton,
R. S.: Chromosomal assignment of the human genes coding for the major
proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins
DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP). Genomics 10:
640-645, 1991.
3. Buxton, R. S.; Wheeler, G. N.; Pidsley, S. C.; Marsden, M. D.;
Adams, M. J.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.: Mouse
desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked
in the proximal region of chromosome 18. Genomics 21: 510-516, 1994.
4. Dua-Awereh, M. B.; Shimomura, Y.; Kraemer, L.; Wajid, M.; Christiano,
A. M.: Mutations in the desmoglein 1 gene in five Pakistani families
with striate palmoplantar keratoderma. J. Derm. Sci. 53: 192-197,
2009.
5. Hennies, H.-C.; Kuster, W.; Mischke, D.; Reis, A.: Localization
of a locus for the striated form of palmoplantar keratoderma to chromosome
18q near the desmosomal cadherin gene cluster. Hum. Molec. Genet. 4:
1015-1020, 1995.
6. Hershkovitz, D.; Lugassy, J.; Indelman, M.; Bergman, R.; Sprecher,
E.: Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin.
Exp. Derm. 34: 224-228, 2008.
7. Hunt, D. M.; Rickman, L.; Whittock, N. V.; Eady, R. A. J.; Simrak,
D.; Dopping-Hepenstal, P. J. C.; Stevens, H. P.; Armstrong, D. K.
B.; Hennies, H. C.; Kuster, W.; Hughes, A. E.; Arnemann, J.; Leigh,
I. M.; McGrath, J. A.; Kelsell, D. P.; Buxton, R. S.: Spectrum of
dominant mutations in the desmosomal cadherin desmoglein 1, causing
the skin disease striate palmoplantar keratoderma. Europ. J. Hum.
Genet. 9: 197-203, 2001.
8. Keren, H.; Bergman, R.; Mizrachi, M.; Kashi, Y.; Sprecher, E.:
Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent
nonsense mutation in DSG1. Arch. Derm. 141: 625-628, 2005.
9. Milingou, M.; Wood, P.; Masouye, I.; McLean, W. H.; Borradori,
L.: Focal palmoplantar keratoderma caused by an autosomal dominant
inherited mutation in the desmoglein 1 gene. Dermatology 212: 117-122,
2006.
10. Rickman, L.; Simrak, D.; Stevens, H. P.; Hunt, D. M.; King, I.
A.; Bryant, S. P.; Eady, R. A. J.; Leigh, I. M.; Arnemann, J.; Magee,
A. I.; Kelsell, D. P.; Buxton, R. S.: N-terminal deletion in a desmosomal
cadherin causes the autosomal dominant skin disease striate palmoplantar
keratoderma. Hum. Molec. Genet. 8: 971-976, 1999.
11. Samuelov, L.; Sarig, O.; Harmon, R. M.; Rapaport, D.; Ishida-Yamamoto,
A.; Isakov, O.; Koetsier, J. L.; Gat, A.; Goldberg, I.; Bergman, R.;
Spiegel, R.; Eytan, O.; and 14 others: Desmoglein 1 deficiency
results in severe dermatitis, multiple allergies and metabolic wasting. Nature
Genet. 45: 1244-1248, 2013.
12. Simrak, D.; Cowley, C. M. E.; Buxton, R. S.; Arnemann, J.: Tandem
arrangement of the closely linked desmoglein genes on human chromosome
18. Genomics 25: 591-594, 1995.
13. Wang, Y.; Amagai, M.; Minoshima, S.; Sakai, K.; Green, K. J.;
Nishikawa, T.; Shimizu, N.: The human genes for desmogleins (DSG1
and DSG3) are located in a small region on chromosome 18q12. Genomics 20:
492-495, 1994.
14. Warren, S. J. P.; Lin, M.-S.; Giudice, G. J.; Hoffmann, R. G.;
Hans-Filho, G.; Aoki, V.; Rivitti, E. A.; dos Santos, V.; Diaz, L.
A.: The prevalence of antibodies against desmoglein 1 in endemic
pemphigus foliaceus in Brazil. New Eng. J. Med. 343: 23-30, 2000.
15. Wu, H.; Wang, Z. H.; Yan, A.; Lyle, S.; Fakharzadeh, S.; Wahl,
J. K.; Wheelock, M. J.; Ishikawa, H.; Uitto, J.; Amagai, M.; Stanley,
J. R.: Protection against pemphigus foliaceus by desmoglein 3 in
neonates. New Eng. J. Med. 343: 31-35, 2000.
16. Zamiri, M.; Smith, F. J. D.; Campbell, L. E.; Tetley, L.; Eady,
R. A. J.; Hodgins, M. B.; McLean, W. H. I.; Munro, C. S.: Mutation
in DSG1 causing autosomal dominant striate palmoplantar keratoderma.
(Letter) Brit. J. Derm. 161: 691-720, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 11/20/2013
Marla J. F. O'Neill - updated: 11/1/2013
Michael B. Petersen - updated: 8/20/2001
Victor A. McKusick - updated: 9/6/2000
Victor A. McKusick - updated: 6/1/1999
*FIELD* CD
Victor A. McKusick: 6/20/1991
*FIELD* ED
carol: 11/20/2013
carol: 11/19/2013
alopez: 11/1/2013
carol: 11/1/2013
alopez: 9/21/2012
alopez: 3/25/2003
cwells: 8/23/2001
cwells: 8/20/2001
mcapotos: 9/20/2000
mcapotos: 9/8/2000
mcapotos: 9/6/2000
alopez: 12/7/1999
carol: 6/16/1999
jlewis: 6/7/1999
jlewis: 6/4/1999
terry: 6/1/1999
carol: 10/13/1998
alopez: 8/26/1998
dkim: 6/30/1998
mark: 4/19/1997
terry: 3/7/1995
carol: 4/18/1994
carol: 7/22/1992
supermim: 3/16/1992
carol: 11/11/1991
carol: 6/20/1991
*RECORD*
*FIELD* NO
125670
*FIELD* TI
*125670 DESMOGLEIN 1; DSG1
;;PEMPHIGUS FOLIACEUS ANTIGEN; PFA
*FIELD* TX
DESCRIPTION
read more
The calcium-binding transmembrane glycoproteins DG I (desmoglein; M(r)
150,000) and the related proteins DG II and DG III (desmocollins; see
DSC2, 125645) comprise the major proteins of the urea-insoluble core of
the desmosome. Desmosomes are the most common type of intercellular
junction in vertebrate epithelial cells. Desmosomal proteins can be
divided into 2 groups on the basis of whether they fractionate with the
core or the urea-soluble 'plaque' components (summary by Arnemann et
al., 1991).
GENE STRUCTURE
Hunt et al. (2001) presented the complete exon-intron structure of the
DSG1 gene, which contains 15 exons and spans about 43 kb.
MAPPING
Arnemann et al. (1991) designed a PCR assay for the gene coding for
desmoglein and used it to test human/mouse and human/rat somatic cell
hybrids with different contents of human chromosomes. In this way, they
were able to assign DSG to chromosome 18.
By fluorescence in situ hybridization, Wang et al. (1994) mapped both
the DSG1 gene and the DSG3 gene to 18q12. Furthermore, both of the genes
were localized on a 320-kb genomic fragment separated by pulsed field
gel electrophoresis.
Buxton et al. (1994) demonstrated that the murine homologs of DSC2 and
DSG1 are closely linked in the proximal region of mouse chromosome 18.
From a study of YAC clones, Simrak et al. (1995) found that the DSG1,
DSG2 (125671), and DSG3 genes are clustered within a region of less than
150 kb in 18q12.1. From restriction enzyme analysis, they showed that
the order of the DSG genes and their orientation is as follows:
5-prime--DSG1--DSG3--DSG2--3-prime. The desmoglein isoforms are
expressed in a stratification-related manner in human epidermis, DSG1
being suprabasally expressed and DSG3 at a lower level, while DSG2
expression is weak and basal. Thus there appears to be some
correspondence between the order of the DSG genes on chromosome 18 and
their expression within tissues, raising the possibility that the
organization of the cluster is required for properly regulated gene
expression.
GENE FUNCTION
Amagai et al. (1991) demonstrated that desmoglein-1 is the antigen
target in the autoimmune disease of skin, pemphigus foliaceus; DSG3
(169615) is the antigen target in pemphigus vulgaris.
Pemphigus foliaceus is an autoimmune skin disease mediated by
autoantibodies against desmoglein-1. The endemic form, known as fogo
selvagem, is thought to have an environmental cause. Warren et al.
(2000) performed an epidemiologic study including an area of Brazil,
Limao Verde, with a prevalence of 3.4% of fogo selvagem in the
population. In 59 of 60 patients with the disorder, antibodies against
desmoglein-1 were detected, whereas such antibodies were found in only 3
of 126 normal subjects from the United States and Japan. Antibodies were
also detected in 51 of 93 normal subjects from Limao Verde, and in 54 of
279 normal subjects from surrounding areas. Serum samples obtained 1 to
4 years before the onset of the disease were available for 5 patients;
all 5 had antibodies in the initial serum samples, and the onset of
disease was associated with a marked increase in antibody values. Warren
et al. (2000) concluded that there must be an unknown environmental
agent that initiates production of antibodies against desmoglein-1.
In pregnant women with pemphigus foliaceus, autoantibodies cross the
placenta and bind to the fetal epidermis, but they rarely cause blisters
in neonates. Wu et al. (2000) hypothesized that the coexpression of
desmoglein-3 in the superficial epidermis in neonates (but not in
adults) protects their skin from blistering caused by passively
transferred maternal antibodies against desmoglein-1, with the presence
of desmoglein-3 compensating for the antibody-induced loss of
desmoglein-1. They presented evidence supporting this hypothesis in the
form of observations in human neonatal and adult skin and in transgenic
mice. Transgenic mice expressed desmoglein-3 in both the superficial and
deep layers of the epidermis.
MOLECULAR GENETICS
- Palmoplantar Keratoderma
The N-terminal extracellular domain of the cadherins, calcium-dependent
cell adhesion molecules, has been shown by x-ray crystallography to be
involved in 2 types of interactions: lateral strand dimers and adhesive
dimers. Rickman et al. (1999) described the first mutation in a cadherin
present in desmosome cell junctions that removes a portion of this
highly conserved first extracellular domain (125670.0001). This
mutation, in the DSG1 gene coding for desmoglein-1, resulted in the
deletion of the first and much of the second beta-strand of the first
cadherin repeat and part of the first Ca(2+)-binding site, and would be
expected to compromise strand dimer formation.
The heterozygous mutation identified by Rickman et al. (1999)
(IVS3-1G-A; 125670.0001) occurred in a 3-generation Dutch family with
striate palmoplantar keratoderma type I (PPKS1; 148700) and segregated
with the disease. The mutation caused aberrant splicing of exon 2 to
exon 4, which are in-frame, with the consequent removal of exon 3
encoding part of the prosequence, the mature protein cleavage site, and
part of the first extracellular domain. This mutation emphasized the
importance of this part of the molecule for cadherin function, and of
the DSG1 protein and hence desmosomes in epidermal function. In the
Dutch pedigree, affected individuals were present in 2 generations with
male-to-male transmission. By inference, one member of an earlier
generation was affected but was not clinically diagnosed. Rickman et al.
(1999) concluded that haploinsufficiency was probably a mechanism of the
dominant disorder in the family. The rather mild clinical symptoms could
have been a consequence of the partial efficiency of missplicing and the
fact that affected individuals were heterozygotes, so that only a
fraction of DSG1 was of the abnormal type lacking exon 3.
Hunt et al. (2001) performed sequence analysis in 5 unrelated cases of
keratosis palmoplantaris striata I and identified heterozygous mutations
(in exons 2, 9, and 11) involving extracellular domains of the DSG1
protein (see, e.g., 125670.0002-125670.0004). All the mutations caused
truncated proteins due to nonsense mutations or to deletions or
insertions resulting in frameshifts, and haploinsufficiency was the most
probable mechanism of the dominant inheritance of the disorder.
In a family of Jewish Yemenite origin with autosomal dominant diffuse
PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and
identified a heterozygous nonsense mutation (R26X; 125670.0004) that
segregated completely with the disease. The same mutation had previously
been detected in a sporadic patient with striate PPK (Hunt et al.,
2001).
In a father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma from a consanguineous Libyan family, Milingou
et al. (2006) identified heterozygosity for a frameshift mutation in the
DSG1 gene (125670.0005) that was not found in unaffected family members
or in 50 unrelated controls. The authors noted that the phenotype in
this family extended the spectrum of clinical features associated with
genetic defects in DSG1.
Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with
PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi
origin, and identified 3 different heterozygous truncating mutations
(see, e.g., 125670.0006) that segregated with disease in each family,
respectively. Direct sequencing of cDNA derived from affected skin
failed to reveal a pathogenic mutation, suggesting that PPKS results
from haploinsufficiency for DSG1.
Dua-Awereh et al. (2009) sequenced the DSG1 gene in 5 Pakistani families
segregating autosomal dominant PPKS and identified distinct heterozygous
mutations in each family, including the recurrent R26X mutation
(125670.0004). Consistent with previous reports, all 5 mutations were
predicted to result in premature termination codons.
- Congenital Erythroderma with Palmoplantar Keratoderma, Hypotrichosis,
and Hyper-IgE
In affected members of 2 unrelated consanguineous families with
congenital erythroderma with palmoplantar keratoderma, hypotrichosis,
and hyper-IgE (EPKHE; 615508), Samuelov et al. (2013) identified 2
different homozygous mutations in the DSG1 gene (125670.0008 and
125670.0009). The mutations segregated with disease in each family, and
all heterozygous carriers displayed palmoplantar hyperkeratotic papules
and plaques, primarily in a nonstriated pattern. Functional analysis
showed that both mutations resulted in loss of expression of DSG1 at the
cell membrane.
*FIELD* AV
.0001
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, IVS2AS, G-A, -1
In a 3-generation Dutch family with striate palmoplantar keratoderma
mapping to chromosome 18 (PPKS1; 148700), Rickman et al. (1999) found a
G-to-A transition in the 3-prime splice acceptor site of intron 1 of the
DSG1 gene that segregated with the disease phenotype. This resulted in
an in-frame deletion of exon 3 encoding part of the prosequence, the
mature protein cleavage site, and part of the highly conserved first
extracellular domain. Affected individuals were present over 2
generations in the Dutch kindred, with male-to-male transmission, and by
inference, one member of an earlier generation was affected but was not
clinically diagnosed. Rickman et al. (1999) concluded that
haploinsufficiency was probably a mechanism of the dominant disorder in
this family, and suggested that their rather mild clinical symptoms
might have been a consequence of the partial efficiency of missplicing
and the fact that affected individuals were heterozygotes, so that only
a fraction of DSG1 was of the abnormal type lacking exon 3.
.0002
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, 1-BP INS, 1079C
In an affected member of a German kindred with striate palmoplantar
keratoderma (PPKS1; 148700), originally studied by Hennies et al.
(1995), Hunt et al. (2001) identified heterozygosity for a 1-bp
insertion (c.1079insC) in exon 9 of the DSG1 gene, causing a frameshift
predicted to result in a premature termination codon 6 residues
downstream. The mutation was not found in 50 unrelated ethnically
matched controls.
.0003
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, 1-BP DEL, 1627A
In a proband with striate palmoplantar keratoderma (PPKS1; 148700), Hunt
et al. (2001) identified heterozygosity for a 1-bp deletion (c.1627delA)
in exon 11 of the DSG1 gene, causing a frameshift predicted to result in
a premature termination codon 18 residues downstream. The mutation was
not found in 50 unrelated ethnically matched controls.
.0004
PALMOPLANTAR KERATODERMA I, STRIATE OR DIFFUSE
DSG1, ARG26TER
In a sporadic patient with striate palmoplantar keratoderma (PPKS1;
148700), Hunt et al. (2001) identified heterozygosity for a c.76C-T
transition in exon 2 of the DSG1 gene, resulting in an arg26-to-ter
(R26X) substitution.
In a father and 3 daughters from a family of Jewish Yemenite origin with
diffuse nonstriated palmoplantar keratoderma (see 148700), Keren et al.
(2005) identified heterozygosity for the DSG1 R26X mutation. The
mutation segregated completely with disease in the family. The 3
affected daughters exhibited a milder form of keratoderma than their
father, with lesions primarily on the soles.
In 6 affected members over 3 generations of a Pakistani family with
PPKS, Dua-Awereh et al. (2009) identified heterozygosity for the R26X
mutation in the DSG1 gene.
.0005
PALMOPLANTAR KERATODERMA I, FOCAL
DSG1, 1-BP INS, 121T
In a Libyan father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma (see 148700), Milingou et al. (2006) identified
heterozygosity for a 1-bp insertion (c.121insT) in exon 3 of the DSG1
gene, causing a frameshift predicted to result in a premature
termination codon 10 residues downstream. The mutation was not found in
unaffected family members or in 50 unrelated controls.
.0006
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, GLN201TER
In 5 affected members over 3 generations of a family with striate
palmoplantar keratoderma (PPKS1; 148700) of Jewish Sephardic descent,
Hershkovitz et al. (2008) identified heterozygosity for a c.602C-T
transition in the DSG1 gene, resulting in a gln201-to-ter (Q201X)
substitution in the second extracellular domain. The mutation was not
found in 9 unaffected family members or in 50 population-matched healthy
controls. RT-PCR of a biopsy from affected skin revealed loss of the
mutant transcript, suggesting that PPKS1 occurs as a result of
haploinsufficiency due to nonsense-mediated decay.
.0007
PALMOPLANTAR KERATODERMA I, STRIATE
DSG1, ARG144TER
In a 40-year-old Scottish man with striate palmoplantar keratoderma
(PPKS1; 148700), Zamiri et al. (2009) identified heterozygosity for a
c.430A-T transversion in exon 5 of the DSG1 gene, resulting in an
arg144-to-ter (R144X) substitution. The mutation was present in his
affected daughter but not his unaffected son. Immunohistochemistry of
affected plantar epidermis from the proband showed prominent staining of
DSG1 in the suprabasal, spinous, and lower granular layers.
.0008
ERYTHRODERMA, CONGENITAL, WITH PALMOPLANTAR KERATODERMA, HYPOTRICHOSIS,
AND HYPER-IgE
DSG1, IVS1, G-A, -1
In 2 sisters from a consanguineous Arab Muslim family with congenital
erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE
(EPKHE; 615508), Samuelov et al. (2013) identified homozygosity for a
c.49-1G-A transition in intron 1 of the DSG1 gene. Direct sequencing of
patient cDNA demonstrated skipping of exon 2, which was predicted to
disrupt the DSG1 signal peptide. The parents, who were both heterozygous
for the mutation, displayed palmoplantar hyperkeratosis. Patient
keratinocytes showed DSG1 accumulation in the cytoplasm, particularly
around the nucleus, in contrast to control keratinocytes, which showed
continuous membrane staining for DSG1. Immunostaining also demonstrated
cytoplasmic mislocalization of DSG1 in patient keratinocytes compared to
control biopsies, and double staining for markers of endoplasmic
reticulum, Golgi, and endosome showed partial colocalization of
cytoplasmic DSG1 with these endomembrane compartments in patient cells.
.0009
ERYTHRODERMA, CONGENITAL, WITH PALMOPLANTAR KERATODERMA, HYPOTRICHOSIS,
AND HYPER-IgE
DSG1, 1-BP DEL, 1861G
In affected members of a consanguineous family of Druze descent with
congenital erythroderma with palmoplantar keratoderma, hypotrichosis,
and hyper-IgE (EPKHE; 615508), Samuelov et al. (2013) identified
homozygosity for a 1-bp deletion (c.1861delG) in the DSG1 gene, causing
a frameshift predicted to result in a premature termination codon
(Ala621GlnfsTer3). Patient skin biopsy showed almost absent DSG1 mRNA,
likely reflecting mRNA decay; consistent with this observation,
immunofluorescent staining for DSG1 was also largely negative. All
heterozygous carriers of the deletion exhibited palmoplantar
hyperkeratosis.
*FIELD* RF
1. Amagai, M.; Klaus-Kovtun, V.; Stanley, J. R.: Autoantibodies against
a novel epithelial cadherin in pemphigus vulgaris, a disease of cell
adhesion. Cell 67: 869-877, 1991.
2. Arnemann, J.; Spurr, N. K.; Wheeler, G. N.; Parker, A. E.; Buxton,
R. S.: Chromosomal assignment of the human genes coding for the major
proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins
DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP). Genomics 10:
640-645, 1991.
3. Buxton, R. S.; Wheeler, G. N.; Pidsley, S. C.; Marsden, M. D.;
Adams, M. J.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.: Mouse
desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked
in the proximal region of chromosome 18. Genomics 21: 510-516, 1994.
4. Dua-Awereh, M. B.; Shimomura, Y.; Kraemer, L.; Wajid, M.; Christiano,
A. M.: Mutations in the desmoglein 1 gene in five Pakistani families
with striate palmoplantar keratoderma. J. Derm. Sci. 53: 192-197,
2009.
5. Hennies, H.-C.; Kuster, W.; Mischke, D.; Reis, A.: Localization
of a locus for the striated form of palmoplantar keratoderma to chromosome
18q near the desmosomal cadherin gene cluster. Hum. Molec. Genet. 4:
1015-1020, 1995.
6. Hershkovitz, D.; Lugassy, J.; Indelman, M.; Bergman, R.; Sprecher,
E.: Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin.
Exp. Derm. 34: 224-228, 2008.
7. Hunt, D. M.; Rickman, L.; Whittock, N. V.; Eady, R. A. J.; Simrak,
D.; Dopping-Hepenstal, P. J. C.; Stevens, H. P.; Armstrong, D. K.
B.; Hennies, H. C.; Kuster, W.; Hughes, A. E.; Arnemann, J.; Leigh,
I. M.; McGrath, J. A.; Kelsell, D. P.; Buxton, R. S.: Spectrum of
dominant mutations in the desmosomal cadherin desmoglein 1, causing
the skin disease striate palmoplantar keratoderma. Europ. J. Hum.
Genet. 9: 197-203, 2001.
8. Keren, H.; Bergman, R.; Mizrachi, M.; Kashi, Y.; Sprecher, E.:
Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent
nonsense mutation in DSG1. Arch. Derm. 141: 625-628, 2005.
9. Milingou, M.; Wood, P.; Masouye, I.; McLean, W. H.; Borradori,
L.: Focal palmoplantar keratoderma caused by an autosomal dominant
inherited mutation in the desmoglein 1 gene. Dermatology 212: 117-122,
2006.
10. Rickman, L.; Simrak, D.; Stevens, H. P.; Hunt, D. M.; King, I.
A.; Bryant, S. P.; Eady, R. A. J.; Leigh, I. M.; Arnemann, J.; Magee,
A. I.; Kelsell, D. P.; Buxton, R. S.: N-terminal deletion in a desmosomal
cadherin causes the autosomal dominant skin disease striate palmoplantar
keratoderma. Hum. Molec. Genet. 8: 971-976, 1999.
11. Samuelov, L.; Sarig, O.; Harmon, R. M.; Rapaport, D.; Ishida-Yamamoto,
A.; Isakov, O.; Koetsier, J. L.; Gat, A.; Goldberg, I.; Bergman, R.;
Spiegel, R.; Eytan, O.; and 14 others: Desmoglein 1 deficiency
results in severe dermatitis, multiple allergies and metabolic wasting. Nature
Genet. 45: 1244-1248, 2013.
12. Simrak, D.; Cowley, C. M. E.; Buxton, R. S.; Arnemann, J.: Tandem
arrangement of the closely linked desmoglein genes on human chromosome
18. Genomics 25: 591-594, 1995.
13. Wang, Y.; Amagai, M.; Minoshima, S.; Sakai, K.; Green, K. J.;
Nishikawa, T.; Shimizu, N.: The human genes for desmogleins (DSG1
and DSG3) are located in a small region on chromosome 18q12. Genomics 20:
492-495, 1994.
14. Warren, S. J. P.; Lin, M.-S.; Giudice, G. J.; Hoffmann, R. G.;
Hans-Filho, G.; Aoki, V.; Rivitti, E. A.; dos Santos, V.; Diaz, L.
A.: The prevalence of antibodies against desmoglein 1 in endemic
pemphigus foliaceus in Brazil. New Eng. J. Med. 343: 23-30, 2000.
15. Wu, H.; Wang, Z. H.; Yan, A.; Lyle, S.; Fakharzadeh, S.; Wahl,
J. K.; Wheelock, M. J.; Ishikawa, H.; Uitto, J.; Amagai, M.; Stanley,
J. R.: Protection against pemphigus foliaceus by desmoglein 3 in
neonates. New Eng. J. Med. 343: 31-35, 2000.
16. Zamiri, M.; Smith, F. J. D.; Campbell, L. E.; Tetley, L.; Eady,
R. A. J.; Hodgins, M. B.; McLean, W. H. I.; Munro, C. S.: Mutation
in DSG1 causing autosomal dominant striate palmoplantar keratoderma.
(Letter) Brit. J. Derm. 161: 691-720, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 11/20/2013
Marla J. F. O'Neill - updated: 11/1/2013
Michael B. Petersen - updated: 8/20/2001
Victor A. McKusick - updated: 9/6/2000
Victor A. McKusick - updated: 6/1/1999
*FIELD* CD
Victor A. McKusick: 6/20/1991
*FIELD* ED
carol: 11/20/2013
carol: 11/19/2013
alopez: 11/1/2013
carol: 11/1/2013
alopez: 9/21/2012
alopez: 3/25/2003
cwells: 8/23/2001
cwells: 8/20/2001
mcapotos: 9/20/2000
mcapotos: 9/8/2000
mcapotos: 9/6/2000
alopez: 12/7/1999
carol: 6/16/1999
jlewis: 6/7/1999
jlewis: 6/4/1999
terry: 6/1/1999
carol: 10/13/1998
alopez: 8/26/1998
dkim: 6/30/1998
mark: 4/19/1997
terry: 3/7/1995
carol: 4/18/1994
carol: 7/22/1992
supermim: 3/16/1992
carol: 11/11/1991
carol: 6/20/1991
MIM
148700
*RECORD*
*FIELD* NO
148700
*FIELD* TI
#148700 PALMOPLANTAR KERATODERMA I, STRIATE, FOCAL, OR DIFFUSE; PPKS1
;;KERATOSIS PALMOPLANTARIS STRIATA I;;
read moreSTRIATE PALMOPLANTAR KERATODERMA I; SPPK1;;
KERATODERMA, PALMOPLANTAR, STRIATE FORM I; KPPS1
*FIELD* TX
A number sign (#) is used with this entry because keratosis
palmoplantaris striata I (PPKS1) is caused by heterozygous mutation in
the DSG1 gene (125670) on chromosome 18q12.
DESCRIPTION
Striate palmoplantar keratoderma belongs to a group of skin diseases in
which there is thickening of the skin on the palms and soles. The
striate form is characterized by longitudinal hyperkeratotic lesions
extending the length of each finger to the palm, and hyperkeratotic
lesions are restricted to regions of the body where pressure and
abrasion are greatest (summary by Hunt et al., 2001). Patients with
diffuse or focal forms of keratoderma associated with mutation in the
DSG1 gene have also been reported (Keren et al., 2005; Milingou et al.,
2006).
- Genetic Heterogeneity of Keratosis Palmoplantaris Striata
Type II PPKS (PPKS2; 612908) is caused by mutation in the DSP gene
(125647) on chromosome 6.
Type III PPKS (PPKS3; 607654) is caused by mutation in the keratin-1
gene (KRT1; 139350) on chromosome 12q.
For a general phenotypic description and a discussion of genetic
heterogeneity of palmoplantar keratoderma (PPK), see epidermolytic PPK
(144200).
CLINICAL FEATURES
The lesions of the hands consist of a streak of hyperkeratosis running
the length of each finger and onto the palm. Bologna (1966) reported a
4-generation kindred in which involvement of males predominated in a
striking manner. This disorder is also referred to as the
Brunauer-Fohs-Siemens type of palmoplantar keratoderma.
Hennies et al. (1995) described a German kindred with a striated form of
palmoplantar keratoderma. Affected members of this family showed marked
hyperkeratosis resembling that found in cases of epidermolytic (144200)
and nonepidermolytic (600962) palmoplantar keratoderma.
Keren et al. (2005) studied a 50-year-old man of Jewish Yemenite origin,
who from 3 years of age had thickening of the skin of the palms and
soles accompanied by painful fissures. He had 5 daughters, 3 of whom
displayed a milder form of keratoderma, mainly evident on the soles. His
maternal grandfather, but not his mother, was reported to have been
similarly affected. On examination, he had diffuse hyperkeratosis and
fissuring on the volar surface of the hands and digits and over the
weight-bearing areas of the soles and toes. Mild onycholysis was also
present, with yellowish discoloration of most nails. Hair, teeth,
mucosae, and nonpalmoplantar skin were normal. Histologic examination of
a palmar skin biopsy showed papillomatosis and marked
orthohyperkeratosis in the epidermis, with widening of intercellular
spaces and disadhesion of keratinocytes in the upper spinous and
granular cell layers.
Milingou et al. (2006) reported a father and 2 daughters from a
consanguineous Libyan family with a focal, nonstriated form of
palmoplantar keratoderma. The proband was a 12-year-old girl who had
progressive thickening of her soles from 5 years of age. Examination
revealed thick, yellow, and fissured focal areas of keratosis on sites
of pressure of the soles and toes. Her toenails were relatively small,
slightly ridged, and partially white. Her palms also showed focal areas
of slight keratosis on pressure sites. There were slightly
hyperkeratotic plaques with follicular keratoses on her knees and on the
anterolateral aspect of her ankles. Smooth circumscribed keratoses were
observed over the dorsa of some proximal and distal interphalangeal
joints of her fingers and toes. The angles of her mouth also showed
slight hyperkeratosis. Her 39-year-old father and 6-year-old sister had
similar but less pronounced hyperkeratotic lesions on pressure points of
the soles, whereas the remainder of the physical examination was
unremarkable. Light microscopy of a plantar skin biopsy from the proband
showed marked hyperkeratosis, acanthosis, and papillomatosis; there were
no epidermolytic changes.
Hershkovitz et al. (2008) studied 3 families with striate palmoplantar
keratoderma, including 1 of Jewish Sephardic descent and 2 of Jewish
Ashkenazi origin. All 9 patients displayed focal areas of
hyperkeratosis, involving palms, soles, and the palmar surface of the
fingers. Marked intrafamilial variation was noted. In all cases,
histologic examination of palmoplantar skin biopsies revealed
orthohyperkeratosis, papillomatosis, widening of the intercellular
spaces, and separation of keratinocytes in the upper spinous and
granular cell layers.
Dua-Awereh et al. (2009) analyzed 5 Pakistani families segregating
autosomal dominant PPKS. All affected individuals had hyperkeratosis of
the palms, predominantly on the creases, with linear hyperkeratosis
along the flexor aspects of the fingers. Focal hyperkeratosis was seen
on the plantar surface of the toes as well as the balls and heels of the
feet. The phenotype was more pronounced in areas that undergo frequent
mechanical stress. None of the affected individuals had wooly hair, and
none of the families had a history of cardiomyopathy, early sudden
death, or cancer.
Zamiri et al. (2009) studied a 3-generation Scottish family with the
striate form of palmoplantar keratoderma. The proband was a 40-year-old
man who had painful thickening of the skin on the palms and soles as
well as hyperhidrosis and intermittent associated blistering since
childhood. Examination showed linear hyperkeratosis of the volar aspect
of the fingers, more extensive focal plantar hyperkeratosis, and mild
hyperkeratosis of the knees. His father, paternal uncle, and 8-year-old
daughter were similarly affected. Light microscopy of the affected
plantar epidermis showed acanthosis with mild spongiosis and
intracellular vacuolation, thickened granular layer with hyperkeratosis,
mild upper dermal perivascular chronic inflammatory cell infiltrate, and
suprabasal cell-cell separation. Electron microscopy revealed normal
keratin intermediate filaments but separation of keratinocytes in the
spinous layer.
DIAGNOSIS
Bergman et al. (2010) analyzed biopsies from 4 patients with DSG1
mutations, including the patient with diffuse PPK originally reported by
Keren et al. (2005) and the 3 patients with PPKS previously studied by
Hershkovitz et al. (2008), comparing them to biopsies from 4 patients
with palmoplantar keratoderma and mutations in the SLURP1 gene (606119;
see Mal de Meleda, 248300), 1 patient with pachyonychia congenita type
II (167210) and a mutation in KRT17 (148069), and 1 patient with focal
palmoplantar keratoderma (FNEPPK; 613000) and a mutation in KRT16
(148067). The distinguishing histopathologic features of the cases with
mutations in DSG1 included varying degrees of widening of the
intercellular spaces and partial disadhesion of keratinocytes in the mid
and upper epidermal spinous cell layers, often extending to the granular
cell layer. These findings were not observed in any of the other 6 PPK
cases; Bergman et al. (2010) concluded that widening of intercellular
spaces and disadhesion of epidermal keratinocytes might serve as
histologic clues to PPKs caused by DSG1 mutations.
MAPPING
In a German kindred with PPKS, Hennies et al. (1995) found linkage of
the disorder to markers on chromosome 18q12 with a maximum 2-point lod
score of 3.30 at theta = 0.00 for D18S536. A cluster of genes for
desmosomal cadherins, desmogleins (DSG1, 125670; DSG2, 125671; DSG3,
169615), and desmocollins (DSC1, 125643 and DSC3, 125645) have been
mapped to the same region, making them good candidates for this form of
PPK.
In a family of Jewish Yemenite origin segregating autosomal dominant
diffuse palmoplantar keratoderma, Keren et al. (2005) used
microsatellite markers spanning the 3 known PPKS-associated genes to
establish the haplotypes of 4 affected and 3 unaffected family members.
All affected individuals shared a common 11.4-Mb segment between markers
D18S877 and D18S535 on chromosome 18q12.1, encompassing the DSG1 locus.
By haplotype analysis in a family of Jewish Sephardic descent with PPKS,
Hershkovitz et al. (2008) excluded linkage to the KRT1 and DSP loci; the
analysis was, however, compatible with linkage to DSG1. Haplotype
analysis in another PPKS family, of Jewish Ashkenazi origin, revealed an
8.2-Mb segment common to all patients, between markers D18S877 and
D18S1102, an interval encompassing the DSG1 gene.
MOLECULAR GENETICS
In a Dutch family with striate palmoplantar keratoderma, Rickman et al.
(1999) identified a heterozygous splicing mutation in the gene encoding
desmoglein (125670.0001).
In 5 unrelated patients with PPKS, including an affected member of the
German kindred originally studied by Hennies et al. (1995), Hunt et al.
(2001) analyzed the DSG1 gene and identified heterozygous truncating
mutations in all of them (see, e.g., 125670.0002-125670.0004). The
preponderance of PPKS mutations in the DSG1 gene rather than in another
desmosomal cadherin suggested that desmoglein-1 is a key protein in
desmosome structure and function in the epidermis, and that PPKS
provides a very sensitive measure of correct desmosome function.
In a family of Jewish Yemenite origin with autosomal dominant diffuse
PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and
identified a heterozygous nonsense mutation (R26X; 125670.0004) that
segregated completely with the disease. The same mutation had previously
been detected in a sporadic patient with striate PPK (Hunt et al.,
2001).
In a father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma from a consanguineous Libyan family, Milingou
et al. (2006) identified heterozygosity for a frameshift mutation in the
DSG1 gene (125670.0005) that was not found in unaffected family members
or in 50 unrelated controls. The authors noted that the phenotype in
this family extended the spectrum of clinical features associated with
genetic defects in DSG1.
Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with
PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi
origin, and identified 3 different heterozygous truncating mutations
(see, e.g., 125670.0006) that segregated with disease in each family,
respectively. Direct sequencing of cDNA derived from affected skin
failed to reveal a pathogenic mutation, suggesting that PPKS results
from haploinsufficiency for DSG1.
*FIELD* RF
1. Bergman, R.; Hershkovitz, D.; Fuchs, D.; Indelman, M.; Gadot, Y.;
Sprecher, E.: Disadhesion of epidermal keratinocytes: a histologic
clue to palmoplantar keratodermas caused by DSG1 mutations. J. Am.
Acad. Derm. 62: 107-113, 2010.
2. Bologna, E. I.: Durch vier Generationenen dominant vererblich
geschlechtsgebundene Keratosis palmaris striata (linearia). Derm.
Wschr. 152: 446-457, 1966.
3. Dua-Awereh, M. B.; Shimomura, Y.; Kraemer, L.; Wajid, M.; Christiano,
A. M.: Mutations in the desmoglein 1 gene in five Pakistani families
with striate palmoplantar keratoderma. J. Derm. Sci. 53: 192-197,
2009.
4. Hennies, H.-C.; Kuster, W.; Mischke, D.; Reis, A.: Localization
of a locus for the striated form of palmoplantar keratoderma to chromosome
18q near the desmosomal cadherin gene cluster. Hum. Molec. Genet. 4:
1015-1020, 1995.
5. Hershkovitz, D.; Lugassy, J.; Indelman, M.; Bergman, R.; Sprecher,
E.: Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin.
Exp. Derm. 34: 224-228, 2008.
6. Hunt, D. M.; Rickman, L.; Whittock, N. V.; Eady, R. A. J.; Simrak,
D.; Dopping-Hepenstal, P. J. C.; Stevens, H. P.; Armstrong, D. K.
B.; Hennies, H. C.; Kuster, W.; Hughes, A. E.; Arnemann, J.; Leigh,
I. M.; McGrath, J. A.; Kelsell, D. P.; Buxton, R. S.: Spectrum of
dominant mutations in the desmosomal cadherin desmoglein 1, causing
the skin disease striate palmoplantar keratoderma. Europ. J. Hum.
Genet. 9: 197-203, 2001.
7. Keren, H.; Bergman, R.; Mizrachi, M.; Kashi, Y.; Sprecher, E.:
Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent
nonsense mutation in DSG1. Arch. Derm. 141: 625-628, 2005.
8. Milingou, M.; Wood, P.; Masouye, I.; McLean, W. H.; Borradori,
L.: Focal palmoplantar keratoderma caused by an autosomal dominant
inherited mutation in the desmoglein 1 gene. Dermatology 212: 117-122,
2006.
9. Rickman, L.; Simrak, D.; Stevens, H. P.; Hunt, D. M.; King, I.
A.; Bryant, S. P.; Eady, R. A. J.; Leigh, I. M.; Arnemann, J.; Magee,
A. I.; Kelsell, D. P.; Buxton, R. S.: N-terminal deletion in a desmosomal
cadherin causes the autosomal dominant skin disease striate palmoplantar
keratoderma. Hum. Molec. Genet. 8: 971-976, 1999.
10. Zamiri, M.; Smith, F. J. D.; Campbell, L. E.; Tetley, L.; Eady,
R. A. J.; Hodgins, M. B.; McLean, W. H. I.; Munro, C. S.: Mutation
in DSG1 causing autosomal dominant striate palmoplantar keratoderma.
(Letter) Brit. J. Derm. 161: 691-720, 2009.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Mouth];
Hyperkeratosis at corners of mouth (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Longitudinal hyperkeratotic lesions along flexor surface of each finger,
extending to palm;
Hyperkeratosis of pressure sites of palms and soles;
Hyperkeratotic plaques on anterolateral ankle area (in some patients);
Hyperkeratotic plaques on anterior knee area (in some patients);
Focal hyperkeratosis (in some patients);
Diffuse hyperkeratosis (in some patients);
Hyperhidrosis (in some patients);
HISTOLOGY:;
Hyperkeratosis, marked;
Orthohyperkeratosis;
Acanthosis;
Papillomatosis Hypergranulosis;
Widening of intercellular spaces;
Separation of keratinocytes in upper spinous and granular cell layers;
ELECTRON MICROSCOPY:;
Normal keratin intermediate filaments;
Separation of keratinocytes in spinous layer;
[Nails];
Nail dystrophy, mild (in some patients);
Ridging (in some patients);
Onycholysis, mild (in some patients);
Whitish discoloration (in some patients);
Yellowish discoloration (in some patients)
MISCELLANEOUS:
Male predominance
MOLECULAR BASIS:
Caused by mutation in the gene encoding desmoglein-1 (DSG1, 125670.0001)
*FIELD* CN
Marla J. F. O'Neill - revised: 11/11/2013
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 11/11/2013
alopez: 3/10/2003
*FIELD* CN
Marla J. F. O'Neill - updated: 11/01/2013
Marla J. F. O'Neill - updated: 7/10/2009
Michael B. Petersen - updated: 8/20/2001
Victor A. McKusick - updated: 6/1/1999
Victor A. McKusick - updated: 2/17/1999
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 11/01/2013
carol: 7/13/2009
carol: 7/10/2009
alopez: 3/10/2003
cwells: 10/28/2002
cwells: 8/23/2001
cwells: 8/20/2001
carol: 6/16/1999
jlewis: 6/4/1999
terry: 6/1/1999
carol: 2/26/1999
mgross: 2/25/1999
mgross: 2/23/1999
terry: 2/17/1999
mark: 7/13/1995
mimadm: 11/5/1994
carol: 5/16/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
*RECORD*
*FIELD* NO
148700
*FIELD* TI
#148700 PALMOPLANTAR KERATODERMA I, STRIATE, FOCAL, OR DIFFUSE; PPKS1
;;KERATOSIS PALMOPLANTARIS STRIATA I;;
read moreSTRIATE PALMOPLANTAR KERATODERMA I; SPPK1;;
KERATODERMA, PALMOPLANTAR, STRIATE FORM I; KPPS1
*FIELD* TX
A number sign (#) is used with this entry because keratosis
palmoplantaris striata I (PPKS1) is caused by heterozygous mutation in
the DSG1 gene (125670) on chromosome 18q12.
DESCRIPTION
Striate palmoplantar keratoderma belongs to a group of skin diseases in
which there is thickening of the skin on the palms and soles. The
striate form is characterized by longitudinal hyperkeratotic lesions
extending the length of each finger to the palm, and hyperkeratotic
lesions are restricted to regions of the body where pressure and
abrasion are greatest (summary by Hunt et al., 2001). Patients with
diffuse or focal forms of keratoderma associated with mutation in the
DSG1 gene have also been reported (Keren et al., 2005; Milingou et al.,
2006).
- Genetic Heterogeneity of Keratosis Palmoplantaris Striata
Type II PPKS (PPKS2; 612908) is caused by mutation in the DSP gene
(125647) on chromosome 6.
Type III PPKS (PPKS3; 607654) is caused by mutation in the keratin-1
gene (KRT1; 139350) on chromosome 12q.
For a general phenotypic description and a discussion of genetic
heterogeneity of palmoplantar keratoderma (PPK), see epidermolytic PPK
(144200).
CLINICAL FEATURES
The lesions of the hands consist of a streak of hyperkeratosis running
the length of each finger and onto the palm. Bologna (1966) reported a
4-generation kindred in which involvement of males predominated in a
striking manner. This disorder is also referred to as the
Brunauer-Fohs-Siemens type of palmoplantar keratoderma.
Hennies et al. (1995) described a German kindred with a striated form of
palmoplantar keratoderma. Affected members of this family showed marked
hyperkeratosis resembling that found in cases of epidermolytic (144200)
and nonepidermolytic (600962) palmoplantar keratoderma.
Keren et al. (2005) studied a 50-year-old man of Jewish Yemenite origin,
who from 3 years of age had thickening of the skin of the palms and
soles accompanied by painful fissures. He had 5 daughters, 3 of whom
displayed a milder form of keratoderma, mainly evident on the soles. His
maternal grandfather, but not his mother, was reported to have been
similarly affected. On examination, he had diffuse hyperkeratosis and
fissuring on the volar surface of the hands and digits and over the
weight-bearing areas of the soles and toes. Mild onycholysis was also
present, with yellowish discoloration of most nails. Hair, teeth,
mucosae, and nonpalmoplantar skin were normal. Histologic examination of
a palmar skin biopsy showed papillomatosis and marked
orthohyperkeratosis in the epidermis, with widening of intercellular
spaces and disadhesion of keratinocytes in the upper spinous and
granular cell layers.
Milingou et al. (2006) reported a father and 2 daughters from a
consanguineous Libyan family with a focal, nonstriated form of
palmoplantar keratoderma. The proband was a 12-year-old girl who had
progressive thickening of her soles from 5 years of age. Examination
revealed thick, yellow, and fissured focal areas of keratosis on sites
of pressure of the soles and toes. Her toenails were relatively small,
slightly ridged, and partially white. Her palms also showed focal areas
of slight keratosis on pressure sites. There were slightly
hyperkeratotic plaques with follicular keratoses on her knees and on the
anterolateral aspect of her ankles. Smooth circumscribed keratoses were
observed over the dorsa of some proximal and distal interphalangeal
joints of her fingers and toes. The angles of her mouth also showed
slight hyperkeratosis. Her 39-year-old father and 6-year-old sister had
similar but less pronounced hyperkeratotic lesions on pressure points of
the soles, whereas the remainder of the physical examination was
unremarkable. Light microscopy of a plantar skin biopsy from the proband
showed marked hyperkeratosis, acanthosis, and papillomatosis; there were
no epidermolytic changes.
Hershkovitz et al. (2008) studied 3 families with striate palmoplantar
keratoderma, including 1 of Jewish Sephardic descent and 2 of Jewish
Ashkenazi origin. All 9 patients displayed focal areas of
hyperkeratosis, involving palms, soles, and the palmar surface of the
fingers. Marked intrafamilial variation was noted. In all cases,
histologic examination of palmoplantar skin biopsies revealed
orthohyperkeratosis, papillomatosis, widening of the intercellular
spaces, and separation of keratinocytes in the upper spinous and
granular cell layers.
Dua-Awereh et al. (2009) analyzed 5 Pakistani families segregating
autosomal dominant PPKS. All affected individuals had hyperkeratosis of
the palms, predominantly on the creases, with linear hyperkeratosis
along the flexor aspects of the fingers. Focal hyperkeratosis was seen
on the plantar surface of the toes as well as the balls and heels of the
feet. The phenotype was more pronounced in areas that undergo frequent
mechanical stress. None of the affected individuals had wooly hair, and
none of the families had a history of cardiomyopathy, early sudden
death, or cancer.
Zamiri et al. (2009) studied a 3-generation Scottish family with the
striate form of palmoplantar keratoderma. The proband was a 40-year-old
man who had painful thickening of the skin on the palms and soles as
well as hyperhidrosis and intermittent associated blistering since
childhood. Examination showed linear hyperkeratosis of the volar aspect
of the fingers, more extensive focal plantar hyperkeratosis, and mild
hyperkeratosis of the knees. His father, paternal uncle, and 8-year-old
daughter were similarly affected. Light microscopy of the affected
plantar epidermis showed acanthosis with mild spongiosis and
intracellular vacuolation, thickened granular layer with hyperkeratosis,
mild upper dermal perivascular chronic inflammatory cell infiltrate, and
suprabasal cell-cell separation. Electron microscopy revealed normal
keratin intermediate filaments but separation of keratinocytes in the
spinous layer.
DIAGNOSIS
Bergman et al. (2010) analyzed biopsies from 4 patients with DSG1
mutations, including the patient with diffuse PPK originally reported by
Keren et al. (2005) and the 3 patients with PPKS previously studied by
Hershkovitz et al. (2008), comparing them to biopsies from 4 patients
with palmoplantar keratoderma and mutations in the SLURP1 gene (606119;
see Mal de Meleda, 248300), 1 patient with pachyonychia congenita type
II (167210) and a mutation in KRT17 (148069), and 1 patient with focal
palmoplantar keratoderma (FNEPPK; 613000) and a mutation in KRT16
(148067). The distinguishing histopathologic features of the cases with
mutations in DSG1 included varying degrees of widening of the
intercellular spaces and partial disadhesion of keratinocytes in the mid
and upper epidermal spinous cell layers, often extending to the granular
cell layer. These findings were not observed in any of the other 6 PPK
cases; Bergman et al. (2010) concluded that widening of intercellular
spaces and disadhesion of epidermal keratinocytes might serve as
histologic clues to PPKs caused by DSG1 mutations.
MAPPING
In a German kindred with PPKS, Hennies et al. (1995) found linkage of
the disorder to markers on chromosome 18q12 with a maximum 2-point lod
score of 3.30 at theta = 0.00 for D18S536. A cluster of genes for
desmosomal cadherins, desmogleins (DSG1, 125670; DSG2, 125671; DSG3,
169615), and desmocollins (DSC1, 125643 and DSC3, 125645) have been
mapped to the same region, making them good candidates for this form of
PPK.
In a family of Jewish Yemenite origin segregating autosomal dominant
diffuse palmoplantar keratoderma, Keren et al. (2005) used
microsatellite markers spanning the 3 known PPKS-associated genes to
establish the haplotypes of 4 affected and 3 unaffected family members.
All affected individuals shared a common 11.4-Mb segment between markers
D18S877 and D18S535 on chromosome 18q12.1, encompassing the DSG1 locus.
By haplotype analysis in a family of Jewish Sephardic descent with PPKS,
Hershkovitz et al. (2008) excluded linkage to the KRT1 and DSP loci; the
analysis was, however, compatible with linkage to DSG1. Haplotype
analysis in another PPKS family, of Jewish Ashkenazi origin, revealed an
8.2-Mb segment common to all patients, between markers D18S877 and
D18S1102, an interval encompassing the DSG1 gene.
MOLECULAR GENETICS
In a Dutch family with striate palmoplantar keratoderma, Rickman et al.
(1999) identified a heterozygous splicing mutation in the gene encoding
desmoglein (125670.0001).
In 5 unrelated patients with PPKS, including an affected member of the
German kindred originally studied by Hennies et al. (1995), Hunt et al.
(2001) analyzed the DSG1 gene and identified heterozygous truncating
mutations in all of them (see, e.g., 125670.0002-125670.0004). The
preponderance of PPKS mutations in the DSG1 gene rather than in another
desmosomal cadherin suggested that desmoglein-1 is a key protein in
desmosome structure and function in the epidermis, and that PPKS
provides a very sensitive measure of correct desmosome function.
In a family of Jewish Yemenite origin with autosomal dominant diffuse
PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and
identified a heterozygous nonsense mutation (R26X; 125670.0004) that
segregated completely with the disease. The same mutation had previously
been detected in a sporadic patient with striate PPK (Hunt et al.,
2001).
In a father and 2 daughters with a focal, nonstriated form of
palmoplantar keratoderma from a consanguineous Libyan family, Milingou
et al. (2006) identified heterozygosity for a frameshift mutation in the
DSG1 gene (125670.0005) that was not found in unaffected family members
or in 50 unrelated controls. The authors noted that the phenotype in
this family extended the spectrum of clinical features associated with
genetic defects in DSG1.
Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with
PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi
origin, and identified 3 different heterozygous truncating mutations
(see, e.g., 125670.0006) that segregated with disease in each family,
respectively. Direct sequencing of cDNA derived from affected skin
failed to reveal a pathogenic mutation, suggesting that PPKS results
from haploinsufficiency for DSG1.
*FIELD* RF
1. Bergman, R.; Hershkovitz, D.; Fuchs, D.; Indelman, M.; Gadot, Y.;
Sprecher, E.: Disadhesion of epidermal keratinocytes: a histologic
clue to palmoplantar keratodermas caused by DSG1 mutations. J. Am.
Acad. Derm. 62: 107-113, 2010.
2. Bologna, E. I.: Durch vier Generationenen dominant vererblich
geschlechtsgebundene Keratosis palmaris striata (linearia). Derm.
Wschr. 152: 446-457, 1966.
3. Dua-Awereh, M. B.; Shimomura, Y.; Kraemer, L.; Wajid, M.; Christiano,
A. M.: Mutations in the desmoglein 1 gene in five Pakistani families
with striate palmoplantar keratoderma. J. Derm. Sci. 53: 192-197,
2009.
4. Hennies, H.-C.; Kuster, W.; Mischke, D.; Reis, A.: Localization
of a locus for the striated form of palmoplantar keratoderma to chromosome
18q near the desmosomal cadherin gene cluster. Hum. Molec. Genet. 4:
1015-1020, 1995.
5. Hershkovitz, D.; Lugassy, J.; Indelman, M.; Bergman, R.; Sprecher,
E.: Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin.
Exp. Derm. 34: 224-228, 2008.
6. Hunt, D. M.; Rickman, L.; Whittock, N. V.; Eady, R. A. J.; Simrak,
D.; Dopping-Hepenstal, P. J. C.; Stevens, H. P.; Armstrong, D. K.
B.; Hennies, H. C.; Kuster, W.; Hughes, A. E.; Arnemann, J.; Leigh,
I. M.; McGrath, J. A.; Kelsell, D. P.; Buxton, R. S.: Spectrum of
dominant mutations in the desmosomal cadherin desmoglein 1, causing
the skin disease striate palmoplantar keratoderma. Europ. J. Hum.
Genet. 9: 197-203, 2001.
7. Keren, H.; Bergman, R.; Mizrachi, M.; Kashi, Y.; Sprecher, E.:
Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent
nonsense mutation in DSG1. Arch. Derm. 141: 625-628, 2005.
8. Milingou, M.; Wood, P.; Masouye, I.; McLean, W. H.; Borradori,
L.: Focal palmoplantar keratoderma caused by an autosomal dominant
inherited mutation in the desmoglein 1 gene. Dermatology 212: 117-122,
2006.
9. Rickman, L.; Simrak, D.; Stevens, H. P.; Hunt, D. M.; King, I.
A.; Bryant, S. P.; Eady, R. A. J.; Leigh, I. M.; Arnemann, J.; Magee,
A. I.; Kelsell, D. P.; Buxton, R. S.: N-terminal deletion in a desmosomal
cadherin causes the autosomal dominant skin disease striate palmoplantar
keratoderma. Hum. Molec. Genet. 8: 971-976, 1999.
10. Zamiri, M.; Smith, F. J. D.; Campbell, L. E.; Tetley, L.; Eady,
R. A. J.; Hodgins, M. B.; McLean, W. H. I.; Munro, C. S.: Mutation
in DSG1 causing autosomal dominant striate palmoplantar keratoderma.
(Letter) Brit. J. Derm. 161: 691-720, 2009.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Mouth];
Hyperkeratosis at corners of mouth (in some patients)
SKIN, NAILS, HAIR:
[Skin];
Longitudinal hyperkeratotic lesions along flexor surface of each finger,
extending to palm;
Hyperkeratosis of pressure sites of palms and soles;
Hyperkeratotic plaques on anterolateral ankle area (in some patients);
Hyperkeratotic plaques on anterior knee area (in some patients);
Focal hyperkeratosis (in some patients);
Diffuse hyperkeratosis (in some patients);
Hyperhidrosis (in some patients);
HISTOLOGY:;
Hyperkeratosis, marked;
Orthohyperkeratosis;
Acanthosis;
Papillomatosis Hypergranulosis;
Widening of intercellular spaces;
Separation of keratinocytes in upper spinous and granular cell layers;
ELECTRON MICROSCOPY:;
Normal keratin intermediate filaments;
Separation of keratinocytes in spinous layer;
[Nails];
Nail dystrophy, mild (in some patients);
Ridging (in some patients);
Onycholysis, mild (in some patients);
Whitish discoloration (in some patients);
Yellowish discoloration (in some patients)
MISCELLANEOUS:
Male predominance
MOLECULAR BASIS:
Caused by mutation in the gene encoding desmoglein-1 (DSG1, 125670.0001)
*FIELD* CN
Marla J. F. O'Neill - revised: 11/11/2013
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 11/11/2013
alopez: 3/10/2003
*FIELD* CN
Marla J. F. O'Neill - updated: 11/01/2013
Marla J. F. O'Neill - updated: 7/10/2009
Michael B. Petersen - updated: 8/20/2001
Victor A. McKusick - updated: 6/1/1999
Victor A. McKusick - updated: 2/17/1999
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 11/01/2013
carol: 7/13/2009
carol: 7/10/2009
alopez: 3/10/2003
cwells: 10/28/2002
cwells: 8/23/2001
cwells: 8/20/2001
carol: 6/16/1999
jlewis: 6/4/1999
terry: 6/1/1999
carol: 2/26/1999
mgross: 2/25/1999
mgross: 2/23/1999
terry: 2/17/1999
mark: 7/13/1995
mimadm: 11/5/1994
carol: 5/16/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989