G2Cdb::Gene report

Gene id
G00001856
Gene symbol
DSG1 (HGNC)
Species
Homo sapiens
Description
desmoglein 1
Orthologue
G00000607 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000068752 (Vega human gene)
Gene
ENSG00000134760 (Ensembl human gene)
1828 (Entrez Gene)
91 (G2Cdb plasticity & disease)
DSG1 (GeneCards)
Literature
125670 (OMIM)
Marker Symbol
HGNC:3048 (HGNC)
Protein Sequence
Q02413 (UniProt)

Synonyms (1)

  • CDHF4

Diseases (3)

Disease Nervous effect Mutations Found Literature Mutations Type Genetic association?
D00000250: Striate palmoplantar keratoderma N Y (11313759) Single nucleotide insertion (SNI) Y
D00000250: Striate palmoplantar keratoderma N Y (11313759) Single nucleotide deletion (SND) Y
D00000250: Striate palmoplantar keratoderma N Y (11313759) Single nucleotide polymorphism (SNP) Y
D00000246: Pemphigus foliaceus N Y (12209366) Single nucleotide polymorphism (SNP) Y
D00000249: Striate keratoderma N Y (12930313) Nonsense (No) Y

References

  • A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma.

    Kljuic A, Gilead L, Martinez-Mir A, Frank J, Christiano AM and Zlotogorski A

    Department of Genetics and Development, Columbia University, New York, NY, USA.

    Striate keratodermas (PPKS) (OMIM 148700) are a rare group of autosomal dominant genodermatoses characterized by palmoplantar keratoderma typified by streaking hyperkeratosis along each finger and extending onto the palm of the hand. We report a four-generation kindred originating from Iran-Syria in which three members were affected with PPKS. Clinically, these patients present with hyperkeratotic palms and plantar plaques. Direct DNA sequencing analysis revealed a heterozygous C-to-A transversion at nt 395 of the DSG1 gene. This mutation converted a serine residue (TCA) in exon 5 to a nonsense mutation (TAA) designated S132X. The mutation identified in this study is a novel mutation in the DSG1 gene and extends the body of evidence implicating the desmoglein gene family in the pathogenesis of human skin disorders.

    Funded by: NIAMS NIH HHS: P30-AR44535; PHS HHS: R01 44924

    Experimental dermatology 2003;12;4;523-7

  • Tunisian endemic pemphigus foliaceus is associated with desmoglein 1 gene polymorphism.

    Ayed MB, Martel P, Zitouni M, Gilbert D, Turki H, Mokni M, Osman AB, Kamoun MR, Zahaf A, Makni S, Masmoudi H and Tron F

    Laboratoire d'Immunologie, CHU Hedi Chaker, Sfax, Tunisia.

    Desmoglein 1 is the target antigen and probably the initiating immunogen of the autoantibody response in pemphigus foliaceus (PF), a blistering autoimmune skin disease. We previously showed that the desmoglein 1 gene (DSG1) is polymorphic and that one of its variants is associated with the sporadic form of PF observed in France. Herewith, we report, based on a case-control analysis, that the same DSG1 polymorphism participates in susceptibility to the endemic form of PF seen in Tunisia and, thus, show that common genetic factors govern the breakage of tolerance to desmoglein 1 in different epidemiological and environmental situations.

    Genes and immunity 2002;3;6;378-9

  • Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.

    Hunt DM, Rickman L, Whittock NV, Eady RA, Simrak D, Dopping-Hepenstal PJ, Stevens HP, Armstrong DK, Hennies HC, Küster W, Hughes AE, Arnemann J, Leigh IM, McGrath JA, Kelsell DP and Buxton RS

    Division of Membrane Biology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK.

    The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

    European journal of human genetics : EJHG 2001;9;3;197-203

Literature (58)

Pubmed - human_disease

  • A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma.

    Kljuic A, Gilead L, Martinez-Mir A, Frank J, Christiano AM and Zlotogorski A

    Department of Genetics and Development, Columbia University, New York, NY, USA.

    Striate keratodermas (PPKS) (OMIM 148700) are a rare group of autosomal dominant genodermatoses characterized by palmoplantar keratoderma typified by streaking hyperkeratosis along each finger and extending onto the palm of the hand. We report a four-generation kindred originating from Iran-Syria in which three members were affected with PPKS. Clinically, these patients present with hyperkeratotic palms and plantar plaques. Direct DNA sequencing analysis revealed a heterozygous C-to-A transversion at nt 395 of the DSG1 gene. This mutation converted a serine residue (TCA) in exon 5 to a nonsense mutation (TAA) designated S132X. The mutation identified in this study is a novel mutation in the DSG1 gene and extends the body of evidence implicating the desmoglein gene family in the pathogenesis of human skin disorders.

    Funded by: NIAMS NIH HHS: P30-AR44535; PHS HHS: R01 44924

    Experimental dermatology 2003;12;4;523-7

  • Tunisian endemic pemphigus foliaceus is associated with desmoglein 1 gene polymorphism.

    Ayed MB, Martel P, Zitouni M, Gilbert D, Turki H, Mokni M, Osman AB, Kamoun MR, Zahaf A, Makni S, Masmoudi H and Tron F

    Laboratoire d'Immunologie, CHU Hedi Chaker, Sfax, Tunisia.

    Desmoglein 1 is the target antigen and probably the initiating immunogen of the autoantibody response in pemphigus foliaceus (PF), a blistering autoimmune skin disease. We previously showed that the desmoglein 1 gene (DSG1) is polymorphic and that one of its variants is associated with the sporadic form of PF observed in France. Herewith, we report, based on a case-control analysis, that the same DSG1 polymorphism participates in susceptibility to the endemic form of PF seen in Tunisia and, thus, show that common genetic factors govern the breakage of tolerance to desmoglein 1 in different epidemiological and environmental situations.

    Genes and immunity 2002;3;6;378-9

  • Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.

    Hunt DM, Rickman L, Whittock NV, Eady RA, Simrak D, Dopping-Hepenstal PJ, Stevens HP, Armstrong DK, Hennies HC, Küster W, Hughes AE, Arnemann J, Leigh IM, McGrath JA, Kelsell DP and Buxton RS

    Division of Membrane Biology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK.

    The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

    European journal of human genetics : EJHG 2001;9;3;197-203

Pubmed - other

  • Antigen selection of anti-DSG1 autoantibodies during and before the onset of endemic pemphigus foliaceus.

    Qian Y, Clarke SH, Aoki V, Hans-Filhio G, Rivitti EA and Diaz LA

    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is characterized by pathogenic anti-desmoglein 1 (DSG1) autoantibodies. To study the etiology of FS, hybridomas that secrete either IgM or IgG (predominantly IgG1 subclass) autoantibodies were generated from the B cells of eight FS patients and one individual 4 years before FS onset, and the H and L chain V genes of anti-DSG1 autoantibodies were analyzed. Multiple lines of evidence suggest that these anti-DSG1 autoantibodies are antigen selected. First, clonally related sets of anti-DSG1 hybridomas characterize the response in individual FS patients. Second, H and L chain V gene use seems to be biased, particularly among IgG hybridomas, and third, most hybridomas are mutants and exhibit a bias in favor of CDR (complementary determining region) amino acid replacement (R) mutations. Strikingly, pre-FS hybridomas also exhibit evidence of antigen selection, including an overlap in V(H) gene use and shared multiple R mutations with anti-DSG1 FS hybridomas, suggesting selection by the same or a similar antigen. We conclude that the anti-DSG1 response in FS is antigen driven and that selection for mutant anti-DSG1 B cells begins well before the onset of disease.

    Funded by: NIAID NIH HHS: R01 AI043587, R01 AI043587-10, R01-AI43587; NIAMS NIH HHS: R01 AR032081, R01 AR032081-27, R01 AR032599, R01 AR032599-27, R01-AR30281, R01-AR32599, T32 AR007369, T32 AR007369-25, T32 AR07369

    The Journal of investigative dermatology 2009;129;12;2823-34

  • Desmocollin 3-mediated binding is crucial for keratinocyte cohesion and is impaired in pemphigus.

    Spindler V, Heupel WM, Efthymiadis A, Schmidt E, Eming R, Rankl C, Hinterdorfer P, Müller T, Drenckhahn D and Waschke J

    Institute of Anatomy and Cell Biology, University of Wuerzburg, Koellikerstrasse 6, D-97070 Wuerzburg, Germany.

    Desmocollin (Dsc) 1-3 and desmoglein (Dsg) 1-4, transmembrane proteins of the cadherin family, form the adhesive core of desmosomes. Here we provide evidence that Dsc3 homo- and heterophilic trans-interaction is crucial for epidermal integrity. Single molecule atomic force microscopy (AFM) revealed homophilic trans-interaction of Dsc3. Dsc3 displayed heterophilic interaction with Dsg1 but not with Dsg3. A monoclonal antibody targeted against the extracellular domain reduced homophilic and heterophilic binding as measured by AFM, caused intraepidermal blistering in a model of human skin, and a loss of intercellular adhesion in cultured keratinocytes. Because autoantibodies against Dsg1 are associated with skin blistering in pemphigus, we characterized the role of Dsc3 binding for pemphigus pathogenesis. In contrast to AFM experiments, laser tweezer trapping revealed that pemphigus autoantibodies reduced binding of Dsc3-coated beads to the keratinocyte cell surface. These data indicate that loss of heterophilic Dsc3/Dsg1 binding may contribute to pemphigus skin blistering.

    The Journal of biological chemistry 2009;284;44;30556-64

  • Anti-desmoglein 1 antibodies in healthy related and unrelated subjects and patients with pemphigus foliaceus in endemic and non-endemic areas from Tunisia.

    Abida O, Kallel-Sellami M, Joly P, Ben Ayed M, Zitouni M, Masmoudi A, Mokni M, Fezzaa B, Ben Osman A, Kammoun MR, Gilbert D, Turki H, Tron F, Masmoudi H, Makni S and Franco-Tunisian Group of Survey and Research on Pemphigus

    Immunology Department, Habib Bourguiba Hospital, Sfax, Tunisia. olfaabida@yahoo.fr

    Background: Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1.

    Aim: To determine the prevalence of anti-desmoglein 1 antibodies in healthy subjects and their distribution in the different regions of Tunisia and to better identify endemic areas of pemphigus foliaceus.

    Methods: We tested, by enzyme-linked immunoserbent assay, sera of 270 normal subjects recruited from different Tunisian areas and 203 related healthy relatives to 90 Tunisian pemphigus foliaceus patients. Results Seventy-six patients (84.4%), 20 healthy controls (7.4%), and 32 relatives (15.76%) had anti-desmoglein 1 antibodies. In southern regions where pemphigus foliaceus is associated with a significant sex ratio imbalance (9 female : 1 male in the south vs. 2.3 : 1 in the north) and a lower mean age of disease onset (33.5 in the south vs. 45 years in the north), a higher prevalence of anti-desmoglein 1 antibodies in healthy controls was observed (9.23% vs. 5.71% in the north). Interestingly, the highest prevalence of anti-desmoglein 1 antibodies in healthy relatives (up to 22%) was observed in the most rural southern localities. More than half anti-desmoglein 1-positive healthy controls were living in rural conditions with farming as occupation, which suggests that this activity may expose the subjects to particular environmental conditions.

    Conclusion: These results show that the endemic features of Tunisian pemphigus foliaceus are focused in these southern areas more than in other areas and that both environmental and genetic factors contribute to the disease.

    Journal of the European Academy of Dermatology and Venereology : JEADV 2009;23;9;1073-8

  • Defining the human deubiquitinating enzyme interaction landscape.

    Sowa ME, Bennett EJ, Gygi SP and Harper JW

    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

    Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.

    Funded by: NIA NIH HHS: AG085011, R01 AG011085, R01 AG011085-16; NIDDK NIH HHS: K01 DK098285; NIGMS NIH HHS: GM054137, GM67945, R01 GM054137, R01 GM054137-14, R01 GM067945

    Cell 2009;138;2;389-403

  • Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis.

    Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Dusek RL, Cornwell M and Green KJ

    Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

    Dsg1 (desmoglein 1) is a member of the cadherin family of Ca(2+)-dependent cell adhesion molecules that is first expressed in the epidermis as keratinocytes transit out of the basal layer and becomes concentrated in the uppermost cell layers of this stratified epithelium. In this study, we show that Dsg1 is not only required for maintaining epidermal tissue integrity in the superficial layers but also supports keratinocyte differentiation and suprabasal morphogenesis. Dsg1 lacking N-terminal ectodomain residues required for adhesion remained capable of promoting keratinocyte differentiation. Moreover, this capability did not depend on cytodomain interactions with the armadillo protein plakoglobin or coexpression of its companion suprabasal cadherin, Dsc1 (desmocollin 1). Instead, Dsg1 was required for suppression of epidermal growth factor receptor-Erk1/2 (extracellular signal-regulated kinase 1/2) signaling, thereby facilitating keratinocyte progression through a terminal differentiation program. In addition to serving as a rigid anchor between adjacent cells, this study implicates desmosomal cadherins as key components of a signaling axis governing epithelial morphogenesis.

    Funded by: NCI NIH HHS: CA122151, P30 CA060553-159026, R01 CA122151, T32 CA009151; NIAMS NIH HHS: AR43380, R01 AR041836, R01 AR043380, R37 AR043380; NIEHS NIH HHS: F30 ES014990, F30 ES14990; NIGMS NIH HHS: T32 GM008061, T32 GM08061

    The Journal of cell biology 2009;185;7;1243-58

  • Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma.

    Dua-Awereh MB, Shimomura Y, Kraemer L, Wajid M and Christiano AM

    Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street VC-1526, New York, NY 10032, United States.

    Background: Striate palmoplantar keratoderma (SPPK; OMIM #148700) is a rare autosomal dominant genodermatosis characterized by linear hyperkeratosis on the digits and hyperkeratosis on the palms and soles. SPPK is known to be caused by heterozygous mutations in either the desmoglein 1 (DSG1), desmoplakin (DSP), or keratin 1 (KRT1) genes.

    Objective: To define the molecular basis of SPPK in five Pakistani families showing a clear autosomal dominant inheritance pattern of SPPK.

    Methods: Based on previous reports of DSG1 mutations in SPPK, we performed direct sequencing of the DSG1 gene of all five families.

    Results: Mutation analysis resulted in the identification of one recurrent mutation (p.R26X) and four novel mutations (c.Ivs4-2A>G, c.515C>T, c.Ivs9-3C>G, and c.1399delA) in the DSG1 gene. Each mutation is predicted to cause haploinsufficiency of DSG1 protein.

    Conclusion: The results of our study further underscore the significance of the desmoglein gene family in diseases of epidermal integrity.

    Funded by: NIAMS NIH HHS: R01 AR044924, R01 AR044924-09, R01 AR44924

    Journal of dermatological science 2009;53;3;192-7

  • Novel mutations in DSG1 causing striate palmoplantar keratoderma.

    Hershkovitz D, Lugassy J, Indelman M, Bergman R and Sprecher E

    Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Health Care Campus, Haifa, Israel.

    Background: Striate palmoplantar keratoderma (SPPK) has been shown to be caused by mutations in at least three genes: DSG1, DSP and KRT1.

    Methods: Three families with nine affected members were assessed using a candidate gene-based screening approach.

    Results: In all three families, new heterozygous mutations were found in DSG1.

    Conclusion: Direct sequencing of cDNA derived from affected skin in one patient failed to reveal a pathogenic mutation, suggesting that SPPK results from haploinsufficiency for DSG1.

    Clinical and experimental dermatology 2009;34;2;224-8

  • The desmoglein-specific cytoplasmic region is intrinsically disordered in solution and interacts with multiple desmosomal protein partners.

    Kami K, Chidgey M, Dafforn T and Overduin M

    University of Birmingham, UK.

    The desmoglein-specific cytoplasmic region (DSCR) is a conserved region of unknown structure and function that uniquely defines the desmoglein family of cell adhesion molecules. It is the site of caspase cleavage during apoptosis, and its mutation is linked to cardiomyopathy. Here, we reveal that a 276-residue DSCR construct of human desmoglein 1 is intrinsically disordered and forms an interaction hub for desmosomal proteins. In solution, it contains 6.5% helical and 10.3% beta-strand structure based on circular dichroism spectroscopy. A single monomeric state with a predominantly unfolded structure is found by size-exclusion chromatography and analytical ultracentrifugation. Thermal stability assays and nuclear magnetic resonance spectroscopy reveal a nonglobular structure under a range of solution conditions. However, the introduction of detergent micelles increases structure to 18% helical and 16% beta-strand character, suggesting an inducible structure. The DSCR exhibits weak but specific interactions with plakoglobin, the plakin domain of desmoplakin, plakophilin 1, and the cytoplasmic domain of desmocollin 1. The desmoglein 1 membrane proximal region also interacts with all four DSCR ligands, strongly with plakoglobin and plakophilin and more weakly with desmoplakin and desmocollin 1. Thus, the DSCR is an intrinsically disordered functional domain with an inducible structure that, along with the membrane proximal region, forms a flexible scaffold for cytoplasmic assembly at the desmosome.

    Funded by: Biotechnology and Biological Sciences Research Council; Cancer Research UK; Wellcome Trust

    Journal of molecular biology 2009;386;2;531-43

  • Protein kinase C isoenzymes differentially regulate the differentiation-dependent expression of adhesion molecules in human epidermal keratinocytes.

    Szegedi A, Páyer E, Czifra G, Tóth BI, Schmidt E, Kovács L, Blumberg PM and Bíró T

    Department of Dermatology, University of Debrecen, Debrecen, Hungary.

    Epidermal expression of adhesion molecules such as desmogleins (Dsg) and cadherins is strongly affected by the differentiation status of keratinocytes. We have previously shown that certain protein kinase C (PKC) isoforms differentially alter the growth and differentiation of human epidermal HaCaT keratinocytes. In this paper, using recombinant overexpression and RNA interference, we define the specific roles of the different PKC isoenzymes in modulation of expression of adhesion molecules in HaCaT keratinocytes. The level of Dsg1, a marker of differentiating keratinocytes, was antagonistically regulated by two Ca-independent 'novel' nPKC isoforms; i.e. it increased by the differentiation-promoting nPKCdelta and decreased by the growth-promoting nPKCepsilon. The expression of Dsg3 (highly expressed in proliferating epidermal layers) was conversely regulated by these isoenzymes, and was also inhibited by the differentiation inducer Ca-dependent 'conventional' cPKCalpha. Finally, the expression of P-cadherin (a marker of proliferating keratinocytes) was regulated by all of the examined PKCs, also in an antagonistic manner (inhibited by cPKCalpha/nPKCdelta and stimulated by cPKCbeta/nPKCepsilon). Collectively, the presented results strongly argue for the marked, differential, and in some instances antagonistic roles of individual Ca-dependent and Ca-independent PKC isoforms in the regulation of expression of adhesion molecules of desmosomes and adherent junctions in human epidermal keratinocytes.

    Funded by: Intramural NIH HHS: Z01 BC005270

    Experimental dermatology 2009;18;2;122-9

  • Loss of desmoglein 1 expression associated with worse prognosis in head and neck squamous cell carcinoma patients.

    Wong MP, Cheang M, Yorida E, Coldman A, Gilks CB, Huntsman D and Berean K

    Department of Pathology and Genetic Pathology Evaluation Centre of the Prostate Research Centre, University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada.

    Aims: Mucosal squamous cell carcinomas are the most common head and neck malignancies. We hypothesised that over-expression of intracellular signalling proteins and decreased expression of desmoglein molecules would be associated with aggressive tumour behaviour in patients with head and neck squamous cell carcinoma.

    Methods: Seventy-eight cases of head and neck squamous cell carcinoma were immunohistochemically stained for desmoglein 1, desmoglein 2, desmoglein 3, p53, bcl-2, vimentin, cyclin D1, p16, p21, p27, E-cadherin, and E2F-1 in paraffin-embedded tissue blocks in a microarray.

    Results: The disease-specific survival was 56% at 5 years and 49% at 10 years. Expression of the desmoglein isotypes correlated positively with each other except for desmoglein 2 and desmoglein 3, which did not show a significant correlation. Desmoglein 1 and E-cadherin expression also correlated. On univariate analysis, only expression of desmoglein 1 correlated with patient outcome; lack of expression of desmoglein 1 was associated with a significantly worse disease-specific survival (p = 0.035). Hierarchical clustering analysis identified a subgroup of three patients with an immunophenotype distinct from the other tumours, characterised by co-expression of p16, p27, E2F-1 and bcl-2. Further statistical analysis of the prognostic significance of this small subgroup was not possible, but these three patients are alive and well.

    Conclusions: Decreased expression of desmoglein 1 is associated with a worse prognosis in head and neck squamous cell carcinoma patients. Examination of an extended panel of immunomarkers revealed a rare subtype of squamous cell carcinoma characterised by the expression of multiple proliferation-associated markers and the anti-apoptotic protein, bcl-2; determination of the prognostic significance of this subgroup will require study of a larger case series.

    Pathology 2008;40;6;611-6

  • Expression of pemphigus-autoantigen desmoglein 1 in human thymus.

    Mouquet H, Berrih-Aknin S, Bismuth J, Joly P, Gilbert D and Tron F

    INSERM U905, Institut Fédératif de Recherche 23, Rouen, France.

    Desmoglein (Dsg) 1 is a transmembrane glycoprotein of the desmosome allowing cell-cell adhesion between keratinocytes, whose expression is restricted to stratified squamous epithelia-like epidermis. Dsg1 is the target autoantigen of pathogenic autoantibodies produced by pemphigus foliaceus and 50% of pemphigus vulgaris patients in a Dsg1-specific T-cell-dependent pathway. Herewith, we show that mRNA of the DSG1 gene is present in normal human thymus and show by quantitative real-time polymerase chain reaction analysis that the expression of DSG1 transcript increases with age. Although immunoblot analysis on human thymus extracts using different anti-Dsg1 antibodies did not allow to detect the protein, we show by double-immunofluorescence assay that Dsg1 is expressed at protein level by CD19+ CD63+ cells located in the medulla. These data provide another illustration of the thymic expression of a tissue-specific autoantigen involved in an organ-specific autoimmune disease, which may participate in the tolerance acquisition and/or regulation of Dsg1-specific T cells.

    Tissue antigens 2008;71;5;464-70

  • The IgM anti-desmoglein 1 response distinguishes Brazilian pemphigus foliaceus (fogo selvagem) from other forms of pemphigus.

    Diaz LA, Prisayanh PS, Dasher DA, Li N, Evangelista F, Aoki V, Hans-Filho G, dos Santos V, Qaqish BF, Rivitti EA and Cooperative Group on Fogo Selvagem Research

    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ldiaz@med.unc.edu

    Fogo selvagem (FS) and pemphigus foliaceus (PF) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies. Although PF occurs sporadically, FS is endemic in Limao Verde (LV), Brazil (3.4% prevalence). IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of FS patients from Hospital-Campo Grande (n=57), 19% from Hospital-Goiania (n=42), 12% from Hospital-Sao Paulo (n=56), 10% of PF patients from United States (n=20), and 0% of PF patients from Japan (n=20). Pemphigus vulgaris (n=40, USA and Japan), bullous pemphigoid (n=40, USA), and healthy donors (n=55, USA) showed negligible percentages of positive sera. High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerindian populations (42% of 243) as compared with urban donors (14% of 81; P<0.001). More than 50% of healthy donors from LV (n=99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11-15 years), and 29% of donors above age 16. IgM anti-Dsg1 epitopes are Ca2+ and carbohydrate-independent. We propose that IgM anti-Dsg1 are common in FS patients in their native environment and uncommon in other pemphigus phenotypes and in FS patients who migrate to urban hospitals. Recurrent environmental antigenic exposure may lead to IgM and IgG responses that trigger FS. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub.

    Funded by: NIAMS NIH HHS: K01 AR052109, KO1 AR052109, R01-AR30281, R01-AR32599, R03 AR053313, T32 AR07369

    The Journal of investigative dermatology 2008;128;3;667-75

  • Pemphigus IgG causes skin splitting in the presence of both desmoglein 1 and desmoglein 3.

    Spindler V, Drenckhahn D, Zillikens D and Waschke J

    University of Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany.

    According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1- but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting.

    The American journal of pathology 2007;171;3;906-16

  • Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.

    Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Thérien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, Hughes TR, Blanchette M, Price DH and Coulombe B

    Laboratory of Gene Transcription and Proteomics Discovery Platform, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada.

    We have performed a survey of soluble human protein complexes containing components of the transcription and RNA processing machineries using protein affinity purification coupled to mass spectrometry. Thirty-two tagged polypeptides yielded a network of 805 high-confidence interactions. Remarkably, the network is significantly enriched in proteins that regulate the formation of protein complexes, including a number of previously uncharacterized proteins for which we have inferred functions. The RNA polymerase II (RNAP II)-associated proteins (RPAPs) are physically and functionally associated with RNAP II, forming an interface between the enzyme and chaperone/scaffolding proteins. BCDIN3 is the 7SK snRNA methylphosphate capping enzyme (MePCE) present in an snRNP complex containing both RNA processing and transcription factors, including the elongation factor P-TEFb. Our results define a high-density protein interaction network for the mammalian transcription machinery and uncover multiple regulatory factors that target the transcription machinery.

    Funded by: Canadian Institutes of Health Research: 14309-3, 82851-1

    Molecular cell 2007;27;2;262-74

  • Striate palmoplantar keratoderma resulting from a frameshift mutation in the desmoglein 1 gene.

    Barber AG, Wajid M, Columbo M, Lubetkin J and Christiano AM

    Department of Genetics & Development, Columbia University, New York, NY 10032, USA.

    Background: Striate keratodermas (PPKS) are a group of rare autosomal dominant palmoplantar keratodermas, characterized by a thickening of the skin on the palms and soles. PPKS is characterized by hyperkeratosis extending along the length of each finger and on the palm of the hand, as well as by patches of hyperkeratosis on the soles.

    Objective: We report a four-generation Pakistani kindred in which 11 members were affected with PPKS.

    Methods: Based on previous reports of DSG1 mutations in PPKS, we performed direct DNA sequencing analysis.

    Results: Clinically, these patients presented with hyperkeratotic palms and with linear hyperkeratosis on the fingers. Additionally, focal hyperkeratosis was seen on the sole of the toes as well as the ball and heel of the foot. DNA sequencing analysis revealed a heterozygous G-to-T transversion in the 3' splice acceptor site of intron 11 of the DSG1 gene designated 1688 -1 G>T. We predict that this mutation will lead to the skipping of exon 12 which is out of frame (134nt), subsequent degradation of the mutant mRNA by non-sense mediated RNA decay, and haploinsufficiency for DSG1.

    Conclusion: We report a novel splice site mutation in the DSG1 gene in PPKS, which further underscores the significance of the desmoglein gene family in diseases of epidermal integrity.

    Funded by: NIAMS NIH HHS: R01 AR044924, R01 AR044924-06A1, R01 AR44924

    Journal of dermatological science 2007;45;3;161-6

  • Changes in desmoglein 1 expression and subcellular localization in cultured keratinocytes subjected to anti-desmoglein 1 pemphigus autoimmunity.

    Cirillo N, Gombos F and Lanza A

    Regional Center on Craniofacial Malformations-MRI, 1st School of Medicine and Surgery, II University of Naples, Naples, Italy. nicola.cirillo@unina2.it

    The complexity of pemphigus acantholysis together with the weak expression of desmoglein 1 (Dsg1) in cultured keratinocytes have made the study on the pathogenic action of anti-Dsg1 antibodies quite difficult. The pathophysiology of the acantholytic phenomenon could depend on the reduction of Dsg1 adhesion function occurring after its massive internalization or decrease of its synthesis. Here, we have investigated this hypothesis by using sera of patients having antibodies against Dsg1 or monoclonal anti-Dsg1 antibodies to simulate pemphigus autoimmunity in Dsg1-rich keratinocytes. Similar to pemphigus foliaceus (PF) and vulgaris (PV) sera, monoclonal anti-Dsg1 antibodies induced transient internalization of Dsg1 and reduced the adhesion strength among keratinocytes. However, binding of IgG to Dsg1 did not determine its early depletion from the adhesion complexes but reduced the amount of Dsg1 found in the Triton X-100 soluble pool of proteins. Taken together, our results represent the first demonstration that anti-Dsg1 antibodies induce similar alterations on the subcellular distribution of Dsg1 irrespective of the disease where they come from. Furthermore, the present study provides insight into the mechanisms underlying epithelial blistering observed in the skin type of pemphigus.

    Journal of cellular physiology 2007;210;2;411-6

  • Large-scale mapping of human protein-protein interactions by mass spectrometry.

    Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T and Figeys D

    Protana, Toronto, Ontario, Canada.

    Mapping protein-protein interactions is an invaluable tool for understanding protein function. Here, we report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach. The study maps protein interactions for 338 bait proteins that were selected based on known or suspected disease and functional associations. Large-scale immunoprecipitation of Flag-tagged versions of these proteins followed by LC-ESI-MS/MS analysis resulted in the identification of 24,540 potential protein interactions. False positives and redundant hits were filtered out using empirical criteria and a calculated interaction confidence score, producing a data set of 6463 interactions between 2235 distinct proteins. This data set was further cross-validated using previously published and predicted human protein interactions. In-depth mining of the data set shows that it represents a valuable source of novel protein-protein interactions with relevance to human diseases. In addition, via our preliminary analysis, we report many novel protein interactions and pathway associations.

    Molecular systems biology 2007;3;89

  • A truncated alternative spliced isoform of human desmoglein 1 contains a specific T cell epitope binding to the pemphigus foliaceus-associated HLA class II DRbeta1*0102 molecule.

    Mouquet H, Farci S, Joly P, Maillère B, Leblond J, Drouot L, Leprince J, Tonon MC, Loiseau P, Charron D, Tron F and Gilbert D

    Institut National de la Santé et de la Recherche Médicale, Unité 519, Faculté de Médecine et de Pharmacie, 22 boulevard Gambetta, 76183 Rouen Cedex 1, France.

    Desmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4). Two Dsg are targeted by pathogenic autoantibodies produced in the course of autoimmune bullous skin diseases, Dsg1 in pemphigus foliaceus (PF), and Dsg3 and Dsg1 in pemphigus vulgaris. The genetic susceptibility to PF is associated with certain HLA class II alleles, which are thought to participate in disease pathogenesis through their capacity to accommodate autoantigen-derived peptides and present them to autoreactive T cells. So far, a unique isoform of Dsg1 has been described in humans, which includes several immunodominant T cell epitopes. In this study, we describe an alternative transcript of DSG1, which contains a 101-bp insertion corresponding to the 3' end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence. This alternative transcript leads to the synthesis of a truncated isoform of Dsg1 expressed in normal human epidermis. This isoform bears a specific peptide sequence that binds to the PF-associated HLA class II DRbeta1*0102 molecule as shown in a HLA-DR peptide-binding assay, and induces PF T cell proliferation. These data provide an illustration of an autoantigen encoded by alternative spliced transcript that may participate in the pathogenesis of the disease by bearing PF-associated HLA class II restricted-epitope.

    Journal of immunology (Baltimore, Md. : 1950) 2006;177;9;6517-26

  • Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome.

    Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-Hautier J, D'Alessio M, Ishida-Yamamoto A, Bodemer C, Zambruno G and Hovnanian A

    Department of Functional Genetics of Epithelial Diseases, INSERM U563, Toulouse Cedex, France.

    SPINK5 (serine protease inhibitor Kazal-type 5), encoding the protease inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor), is the defective gene in Netherton syndrome (NS), a severe inherited keratinizing disorder. We have recently demonstrated epidermal protease hyperactivity in Spink5(-/-) mice resulting in desmosomal protein degradation. Herein, we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS. We demonstrated that, in a majority of patients, desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) were dramatically reduced in the upper most living layers of the epidermis. These defects were associated with premature degradation of corneodesmosomes. Stratum corneum tryptic enzyme (SCTE)-like and stratum corneum chymotryptic enzyme (SCCE)-like activities were increased, suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins. SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced. In contrast, a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations. This suggests a degree of correlation between cadherin degradation and clinical severity. This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression.

    The Journal of investigative dermatology 2006;126;7;1622-32

  • Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry.

    Ramachandran P, Boontheung P, Xie Y, Sondej M, Wong DT and Loo JA

    Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California, USA.

    Glycoproteins make up a major and important part of the salivary proteome and play a vital role in maintaining the health of the oral cavity. Because changes in the physiological state of a person are reflected as changes in the glycoproteome composition, mapping the salivary glycoproteome will provide insights into various processes in the body. Salivary glycoproteins were identified by the hydrazide coupling and release method. In this approach, glycoproteins were coupled onto a hydrazide resin, the proteins were then digested and formerly N-glycosylated peptides were selectively released with the enzyme PNGase F and analyzed by LC-MS/MS. Employing this method, coupled with in-solution isoelectric focusing separation as an additional means for pre-fractionation, we identified 84 formerly N-glycosylated peptides from 45 unique N-glycoproteins. Of these, 16 glycoproteins have not been reported previously in saliva. In addition, we identified 44 new sites of N-linked glycosylation on the proteins.

    Funded by: NIDCR NIH HHS: U01 DE016275; NIGMS NIH HHS: GM07185

    Journal of proteome research 2006;5;6;1493-503

  • The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes.

    Dusek RL, Getsios S, Chen F, Park JK, Amargo EV, Cryns VL and Green KJ

    Department of Pathology and Dermatology and Cell Death Regulation Laboratory, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

    Although a number of cell adhesion proteins have been identified as caspase substrates, the potential role of differentiation-specific desmosomal cadherins during apoptosis has not been examined. Here, we demonstrate that UV-induced caspase cleavage of the human desmoglein 1 cytoplasmic tail results in distinct 17- and 140- kDa products, whereas metalloproteinase-dependent shedding of the extracellular adhesion domain generates a 75-kDa product. In vitro studies identify caspase-3 as the preferred enzyme that cleaves desmoglein 1 within its unique repeating unit domain at aspartic acid 888, part of a consensus sequence not conserved among the other desmosomal cadherins. Apoptotic processing leads to decreased cell surface expression of desmoglein 1 and re-localization of its C terminus diffusely throughout the cytoplasm over a time course comparable with the processing of other desmosomal proteins and cytoplasmic keratins. Importantly, whereas classic cadherins have been reported to promote cell survival, short hairpin RNA-mediated suppression of desmoglein 1 in differentiated keratinocytes protected cells from UV-induced apoptosis. Collectively, our results identify desmoglein 1 as a novel caspase and metalloproteinase substrate whose cleavage likely contributes to the dismantling of desmosomes during keratinocyte apoptosis and also reveal desmoglein 1 as a previously unrecognized regulator of apoptosis in keratinocytes.

    Funded by: NCI NIH HHS: T32 CA09560; NIAMS NIH HHS: R01AR41836; NIDCR NIH HHS: P01 DE12328

    The Journal of biological chemistry 2006;281;6;3614-24

  • Focal palmoplantar keratoderma caused by an autosomal dominant inherited mutation in the desmoglein 1 gene.

    Milingou M, Wood P, Masouyé I, McLean WH and Borradori L

    Clinic of Dermatology, University Medical Hospital, Rue Micheli-du-Crest 24, CH-1211 Geneva, Switzerland.

    Background: Palmoplantar keratodermas (PPK) encompass a large genetically heterogeneous group of diseases associated with hyperkeratosis of the soles and/or palms that occur either isolated or in association with other cutaneous and extracutaneous manifestations. Pathogenic mutations in the desmoglein 1 gene (DSG1) have recently been identified in a subset of patients with the striate type of PPK.

    Observation: We have identified a patient with a focal non-striated form of PPK associated with discrete troubles of keratinisation at sites exposed to mechanical trauma, such as the knees, ankles or finger knuckles, and with mild nail dystrophy. Genetic analyses disclosed a novel dominantly inherited heterozygous single base insertion in exon 3 of DSG1, 121insT, leading to a premature termination codon. The mutation was also present in the father and in a sister.

    Conclusion: Our observation extends the spectrum of clinical features associated with genetic defects in DSG1 and provides further evidence that perturbation of desmoglein 1 expression has a critical impact on the integrity of tissues experiencing strong mechanical stress.

    Funded by: Medical Research Council: G0700314

    Dermatology (Basel, Switzerland) 2006;212;2;117-22

  • Pemphigus foliaceus and desmoglein 1 gene polymorphism: is there any relationship?

    Petzl-Erler ML and Malheiros D

    Human Molecular Genetics Laboratory, Department of Genetics, Federal University of Paraná, Caixa Postal 19071, 81531-990 Curitiba, Brazil. perler@ufpr.br

    Transmembrane proteins of the cadherin superfamily, the desmogleins and desmocollins, mediate intercellular adhesion in desmosomes. Autoantibodies to desmoglein 1 (dsg1) are a hallmark of pemphigus foliaceus (PF), a disease characterized by skin blistering resulting from keratinocyte cell detachment. The etiology and pathogenesis of this disease remain poorly understood; however, genetic susceptibility is clearly involved. The aim of this study was to verify if genetic variants of dsg1 influence susceptibility/resistance to endemic PF (fogo selvagem). Two single nucleotide polymorphisms (SNPs) were analyzed: 809 (C,T), a synonymous variation, and 1660 (A,C), a tyrosine<-->serine variation in the fifth extracellular domain. Allelic, haplotypic and genotypic frequencies did not differ significantly between the patient (n=134) and the control (n=227) population samples. Moreover, there is no evidence of interaction between the DSG1 and the HLA-DRB1 and IL6 genes, whose alleles had been found associated with differential susceptibility to PF. The results of this study agree with the described and predicted B- and T-cell epitopes of the dsg1 molecule, which seemingly are not affected by the allelic variation. We conclude that genetic diversity of the autoantigen dsg1 is not a major factor for PF pathogenesis in the Brazilian population.

    Journal of autoimmunity 2005;25;2;121-5

  • Ex vivo analysis of desmoglein 1-responsive T-helper (Th) 1 and Th2 cells in patients with pemphigus foliaceus and healthy individuals.

    Gebhard KL, Veldman CM, Wassmuth R, Schultz E, Schuler G and Hertl M

    Department of Dermatology, University of Erlangen, Erlangen, Germany.

    Pemphigus foliaceus (PF) is a severe autoimmune bullous disorder, characterized by autoantibodies (autoAb) against desmoglein 1 (Dsg1). As T cells may be critical in the pathology of PF, the aim of the present study was to identify and characterize autoaggressive T-helper cells reactive to Dsg1 in PF patients and healthy individuals. Eight patients with the clinical diagnosis of PF and six HLA class II-matched healthy individuals were examined. By magnetic cell-sorting (MACS) cytokine-secretion assay, Dsg1-responsive T-helper (Th) 1 and Th2 cells were isolated and cloned by limiting dilution. The generated T-cell clones (TCC) were characterized regarding proliferative response, TCR Vbeta-chain usage, and cytokine profile upon in vitro stimulation with Dsg1. Both Dsg1-reactive Th1 and Th2 cells were detected in PF patients and controls at similar frequencies. A total of 15 Th1 and Th2 clones were isolated from patients and 27 TCC from healthy controls. Analysis of TCR Vbeta-chain usage of autoreactive T cells from both groups revealed no predominance of a specific Vbeta chain. Noteworthy, the isolated TCC showed a polarized Th1- or Th2-like phenotype upon in vitro culture and stable expression of Th1 or Th2 cytokines during long-term in vitro culture. In summary, our data demonstrate that T-cell autoreactivity against Dsg1 is not restricted to patients with PF. Moreover, both Th1 and Th2 cells were present in patients and healthy donors, suggesting that the loss of B-cell tolerance against Dsg1 in PF is not exclusively determined by the presence of autoaggressive T cells.

    Experimental dermatology 2005;14;8;586-92

  • Anti-desmoglein-1 antibodies in onchocerciasis, leishmaniasis and Chagas disease suggest a possible etiological link to Fogo selvagem.

    Diaz LA, Arteaga LA, Hilario-Vargas J, Valenzuela JG, Li N, Warren S, Aoki V, Hans-Filho G, Eaton D, dos Santos V, Nutman TB, de Mayolo AA, Qaqish BF, Sampaio SA, Rivitti EA and Cooperative Group on Fogo Selvagem Research

    Department of Dermatology, University of North Carolina at Chapel Hill, North Carolina, USA. ldiaz@med.unc.edu

    Pemphigus foliaceus (PF) and the endemic form Fogo Selvagem (FS) are mediated by pathogenic antibodies to the EC1-2 domains of desmoglein-1. There is a preclinical phase with antibodies to only EC5. Based on geographic clustering of cases, FS is thought to have an, as yet unidentified, environmental trigger. In this study we have searched for anti-desmoglein-1 antibodies in sera from parasitic (leishmaniasis, Chagas, and onchocerciasis), and infectious diseases (leprosy and South American (SA) blastomycosis), which are prevalent in the same geographic regions of Brazil as FS. A specific and sensitive desmoglein-1 ELISA detected antibodies in 34 of 41 onchocerciasis (83%), 38 of 88 leishmaniasis (43%), 18 of 31 Chagas disease (58%), 7 of 28 SA blastomycosis (25%), and 14 of 83 leprosy sera (17%). These sera recognized epitopes restricted to the EC5 domain. These findings identify several etiological factors for FS. It is hypothesized that a component of insect vector saliva, rather than the parasite itself may trigger an antibody response to EC-5. In persons with the known HLA susceptibility alleles and living in endemic areas, a response to the EC1-2 domains may subsequently develop by epitope spreading with associated clinical signs of FS.

    Funded by: NIAMS NIH HHS: R01 AR032599, R01-AR30281, R01-AR32599, T32 AR07369

    The Journal of investigative dermatology 2004;123;6;1045-51

  • Coordinated expression of desmoglein 1 and desmocollin 1 regulates intercellular adhesion.

    Getsios S, Amargo EV, Dusek RL, Ishii K, Sheu L, Godsel LM and Green KJ

    Department of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

    Desmoglein 1 (Dsg1) is a component of desmosomes present in the upper epidermis and can be targeted by autoimmune antibodies or bacterial toxins, resulting in skin blistering diseases. These defects in tissue integrity are believed to result from compromised desmosomal adhesion; yet, previous attempts to directly test the adhesive roles of desmosomal cadherins using normally non-adherent L cells have yielded mixed results. Here, two complementary approaches were used to better resolve the molecular determinants for Dsg1-mediated adhesion: (1) a tetracycline-inducible system was used to modulate the levels of Dsg1 expressed in L cell lines containing desmocollin 1 (Dsc1) and plakoglobin (PG) and (2) a retroviral gene delivery system was used to introduce Dsg1 into normal human epidermal keratinocytes (NHEK). By increasing Dsg1 expression relative to Dsc1 and PG, we were able to demonstrate that the ratio of Dsg1:Dsc1 is a critical determinant of desmosomal adhesion in fibroblasts. The distribution of Dsg1 was organized at areas of cell-cell contact in the multicellular aggregates that formed in these suspension cultures. Similarly, the introduction of Dsg1 into NHEKs was capable of increasing the aggregation of single cell suspensions and further enhanced the adhesive strength of intact epithelial sheets. Endogenous Dsc1 levels were also increased in NHEKs containing Dsg1, providing further support for the coordination of these two desmosomal cadherins in regulating adhesive structures. These Dsg1-mediated effects on intercellular adhesion were directly related to the presence of an intact extracellular domain as ETA, a toxin that specifically cleaves this desmosomal cadherin, inhibited adhesion in both fibroblasts and keratinocytes. Collectively, these observations demonstrate that Dsg1 promotes the formation of intercellular adhesion complexes and suggest that the relative level of Dsg and Dsc expressed at the cell surface regulates this adhesive process.

    Funded by: NCI NIH HHS: T32 CA09560; NIAMS NIH HHS: R01 AR41836; NIDCR NIH HHS: P01 DE12328

    Differentiation; research in biological diversity 2004;72;8;419-33

  • Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.

    Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, Egelrud T, Simon M and Serre G

    UMR5165 "Epidermis Differentiation and Rheumatoid Autoimmunity", CNRS-P. Sabatier University (Institut Fédératif de Recherche 30 and INSERM-CNRS-Université P. Sabatier-Centre Hospitalier Universitaire), Toulouse, France.

    Corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) are adhesive proteins of the extracellular part of the corneodesmosomes, the junctional structures that mediate corneocyte cohesion. The degradation of these proteins at the epidermis surface is necessary for desquamation. Two serine proteases of the kallikrein family synthesized as inactive precursors have been implicated in this process: the stratum corneum chymotryptic enzyme (SCCE/KLK7/hK7) and the stratum corneum tryptic enzyme (SCTE/KLK5/hK5). Here, we analyzed the capacity of these enzymes to cleave DSG1, DSC1, and epidermal or recombinant forms of CDSN, at an acidic pH close to that of the stratum corneum. SCCE directly cleaved CDSN and DSC1 but was unable to degrade DSG1. But incubation with SCTE induced degradation of the three corneodesmosomal components. Using the recombinant form of CDSN, either with its N-glycan chain or enzymatically deglycosylated, we also demonstrated that oligosaccharide residues do not protect CDSN against proteolysis by SCCE. Moreover, our results suggest that SCTE is able to activate the proform of SCCE. These results strongly suggest that the two kalikreins are involved in desquamation. A model is proposed for desquamation that could be regulated by a precisely controlled protease-protease inhibitor balance.

    The Journal of investigative dermatology 2004;122;5;1235-44

  • Pathogenicity and epitope characteristics of anti-desmoglein-1 from pemphigus foliaceus patients expressing only IgG1 autoantibodies.

    Hacker-Foegen MK, Janson M, Amagai M, Fairley JA and Lin MS

    Department of Dermatology, Medical College of Wisconsin, Milwaukee 53226, USA.

    Pemphigus foliaceus (PF) is an antibody-mediated autoimmune disorder with IgG1 and IgG4 as the predominant subclasses of autoantibodies against a desmosomal glycoprotein, desmoglein-1 (Dsg1). Previously, we found that the IgG4 anti-Dsg1 autoantibodies only recognize a conformational epitope(s), whereas the IgG1 autoantibodies recognize both conformational and linear epitopes but do not display pathogenicity in the passive transfer animal model. The purpose of this study was to analyze the epitopes recognized by autoanti-bodies from a subset of PF patients who only express anti-Dsg1 of the IgG1 isotype throughout the course of their diseases and to further characterize the pathogenicity of their IgG1 anti-Dsg1. We found that IgG1 auto-antibodies in this subset of PF patients, similar to IgG4 autoantibodies from other PF patients, are able to bind both human and mouse skin and induce the experimental PF in mice. Moreover, a detailed epitope mapping reveals that the conformational epitopes recognized by IgG1 autoantibodies from these PF patients are restricted to the first 161 amino acids of Dsg1, whereas the linear epitopes are spread throughout the entire ectodomain. In conclusion, our study reveals that the isotype of IgG does not necessarily determine the epitopes and pathogenicity of pemphigus autoantibodies.

    Funded by: NIAID NIH HHS: R01-AI48348

    The Journal of investigative dermatology 2003;121;6;1373-8

  • Plakoglobin is O-glycosylated close to the N-terminal destruction box.

    Hatsell S, Medina L, Merola J, Haltiwanger R and Cowin P

    Department of Cell Biology, New York University Medical School, New York, New York 10016, USA.

    Plakoglobin provides a key linkage in protein chains that connect desmosomal and classical cadherins to the cytoskeleton. It is also present in a significant cytosolic pool that has the capacity to impact on canonical Wnt signaling by competing for interaction with partner proteins of beta-catenin. The closely related protein, beta-catenin, is rapidly targeted for proteasomal degradation by phosphorylation of a "destruction box" within the N-terminal domain. Inhibition of this process forms the basis of Wnt signaling. This destruction box is also found in the N-terminal domain of plakoglobin. We report that plakoglobin is modified by the addition of O-GlcNAc at a single site in close proximity to the destruction box. O-GlcNAc modification has been proposed to counteract phosphorylation, provide protection from proteasomal degradation, mediate signal transduction, silence transcription, and regulate multimolecular protein assembly. This finding has potential implications for understanding the roles of plakoglobin.

    Funded by: NIGMS NIH HHS: GM47429

    The Journal of biological chemistry 2003;278;39;37745-52

  • Calcium-dependent conformation of desmoglein 1 is required for its cleavage by exfoliative toxin.

    Hanakawa Y, Selwood T, Woo D, Lin C, Schechter NM and Stanley JR

    Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    In bullous impetigo, Staphylococcus aureus spreads under the stratum corneum of skin by elaboration of exfoliative toxin, which hydrolyzes only one peptide bond in a highly structured calcium-binding domain of desmoglein 1, resulting in loss of its function. We investigated the basis of this exquisite specificity. Exfoliative toxin cannot cleave desmoglein 1 pretreated at 56 degrees C or higher or at low or high pH, suggesting that the proper conformation of desmoglein 1 is critical for its cleavage. Because cleavage occurs in an area of desmoglein 1 stabilized by calcium, we determined if the conformation necessary for cleavage is calcium-dependent. Depletion of calcium from desmoglein 1 completely inhibited its cleavage by exfoliative toxin, even after calcium was added back. A change in conformation of desmoglein 1 by calcium depletion was shown, with immunofluorescence and enzyme-linked immunoassay, by loss of binding of PF sera, which recognize conformational epitopes. This change in conformation was confirmed by tryptophan fluorometry and circular dichroism, and was irreversible with repletion of calcium. These data suggest that the specificity of exfoliative toxin cleavage of desmoglein 1 resides not only in simple amino acid sequences but also in its calcium-dependent conformation.

    The Journal of investigative dermatology 2003;121;2;383-9

  • Keratinocyte adherens junctions initiate nuclear signaling by translocation of plakoglobin from the membrane to the nucleus.

    Hu P, Berkowitz P, O'Keefe EJ and Rubenstein DS

    Department of Dermatology, University of North Carolina--Chapel Hill, School of Medicine, Chapel Hill, North Carolina 27599-7287, USA.

    Because changes in cell-cell adhesion have profound effects on cellular behavior, we hypothesized a link between the adhesion and signaling functions of plakoglobin and beta-catenin. To investigate the existence of adherens-junction-mediated signaling, we used peroxovanadate to tyrosine phosphorylate plakoglobin and beta-catenin and to dissociate adherens junctions. The distribution of plakoglobin and beta-catenin was determined by immunofluorescence, western blot analysis, pulse-chase radiolabeling, and biochemical subcellular fractionation. Coimmunoprecipitation studies from nuclear fractions, gel-shift assays, and transient transfections with T cell factor (TCF)/lymphoid enhancer factor (LEF) optimized promoter reporter constructs were used to investigate the ability of plakoglobin and beta-catenin that had redistributed from the membrane to the nucleus to form functional transcriptional regulatory complexes with TCF/LEF family member transcription factors. Tyrosine phosphorylation of plakoglobin and beta-catenin resulted in their rapid translocation from the cell membrane to the nucleus. Nuclear translocation was associated with increased plakoglobin and decreased beta-catenin binding to nuclear TCF/LEF and downregulation of gene transcription from TCF/LEF reporter constructs. These results are consistent with a signaling pathway initiated by structural changes in the adherens junction in which adherens-junction-derived plakoglobin regulates nuclear transcription by antagonizing the binding of beta-catenin to TCF/LEF proteins.

    Funded by: NIAID NIH HHS: R01 AI49427-01

    The Journal of investigative dermatology 2003;121;2;242-51

  • Desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation.

    Wu H, Stanley JR and Cotsarelis G

    Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    Within stratified squamous epithelia, such as the epidermis, desmogleins are generally expressed in a differentiation-specific manner. Similar to the epidermis, the hair follicle is compartmentalized into a hierarchy of cell types based on their level of differentiation. Relatively undifferentiated stem cells in the bulge can generate epidermis, sebaceous gland, and hair bulb matrix cells. The latter give rise to at least six different cell types that keratinize as they move up the hair shaft and inner root sheath. Here, we examined expression patterns of the desmoglein isotypes, desmogleins 1, 2, and 3 in the cutaneous epithelium, and discovered that desmoglein 1 and 2 expression correlated with the state of differentiation of defined populations within the hair follicle. Desmoglein 2 was highly expressed by the least differentiated cells of the cutaneous epithelium, including the hair follicle bulge of the fetus and adult, bulb matrix cells, and basal layer of the outer root sheath. In contrast, desmoglein 1 defined more differentiated cell populations, and was expressed in epidermal suprabasal cells, the inner root sheath, and the innermost layers of the outer root sheath. We found that the expression pattern of desmoglein 3 correlated with different types of keratinization. In areas of trichilemmal keratinization in the follicle, and in cysts arising from these areas, desmoglein 3 was expressed throughout all layers of the outer root sheath and cyst wall. In areas of epidermal-like keratinization, such as in the infundibulum and in epidermal inclusion cysts, desmoglein 3 expression was limited mainly to the basal layer. We conclude that desmoglein expression patterns define compartments of cells in similar states of differentiation within the cutaneous epithelium, and reveal a hierarchy of differentiation among these compartments.

    The Journal of investigative dermatology 2003;120;6;1052-7

  • Defining desmosomal plakophilin-3 interactions.

    Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ and van Roy F

    Molecular Cell Biology Unit, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology (VIB)-Ghent University, B-9000 Ghent, Belgium.

    Plakophilin 3 (PKP3) is a recently described armadillo protein of the desmosomal plaque, which is synthesized in simple and stratified epithelia. We investigated the localization pattern of endogenous and exogenous PKP3 and fragments thereof. The desmosomal binding properties of PKP3 were determined using yeast two-hybrid, coimmunoprecipitation and colocalization experiments. To this end, novel mouse anti-PKP3 mAbs were generated. We found that PKP3 binds all three desmogleins, desmocollin (Dsc) 3a and -3b, and possibly also Dsc1a and -2a. As such, this is the first protein interaction ever observed with a Dsc-b isoform. Moreover, we determined that PKP3 interacts with plakoglobin, desmoplakin (DP) and the epithelial keratin 18. Evidence was found for the presence of at least two DP-PKP3 interaction sites. This finding might explain how lateral DP-PKP interactions are established in the upper layers of stratified epithelia, increasing the size of the desmosome and the number of anchoring points available for keratins. Together, these results show that PKP3, whose epithelial and epidermal desmosomal expression pattern and protein interaction repertoire are broader than those of PKP1 and -2, is a unique multiprotein binding element in the basic architecture of a vast majority of epithelial desmosomes.

    Funded by: NIAMS NIH HHS: AR41836, AR43380, R01 AR041836, R01 AR043380, R37 AR043380; NIDCR NIH HHS: P01 DE012328, P01 DE12328

    The Journal of cell biology 2003;161;2;403-16

  • Desmoglein as a target in autoimmunity and infection.

    Amagai M

    Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, USA. amagai@sc.itc.keio.ac.jp

    Clinical phenotypes of most diseases are complex. However, once the mechanism behind the scene is clarified, the nature shows amazing beauty. There is a simple logic behind a complex disease. The exact molecular mechanism of the blister formation in staphylococcal scalded skin syndrome (SSSS) remained to be elucidated for 3 decades since exfoliative toxin was discovered by Melish and Glasgow in 1970. A knowledge accumulated to understand the pathogenesis of pemphigus and cell-cell adhesion of keratinocytes led us to solve this question. Desmoglein 1, which is a cadherin type cell-cell adhesion molecule in desmosomes, is targeted in two different skin diseases, pemphigus foliaceus, and SSSS. In pemphigus foliaceus IgG autoantibodies are developed against desmoglein 1 and inhibit its adhesive function with resultant blister formation in the superficial epidermis. In SSSS, exfoliative toxin produced by Staphylococcus aureus specifically binds and cleaves desmoglein 1 with resultant blister formation at the identical site.

    Journal of the American Academy of Dermatology 2003;48;2;244-52

  • Differential effects of desmoglein 1 and desmoglein 3 on desmosome formation.

    Hanakawa Y, Amagai M, Shirakata Y, Yahata Y, Tokumaru S, Yamasaki K, Tohyama M, Sayama K and Hashimoto K

    Department of Dermatology, School of Medicine, Ehime University, Ehime, Japan. hanakawa@m.ehime-u.ac.jp

    The desmoglein plays an important part in the formation of desmosomes. We constructed recombinant adenoviruses containing desmoglein 1 and desmoglein 3 derivatives partly lacking the extracellular domain (desmoglein 1DeltaEC and desmoglein 3DeltaEC, respectively), and full-length desmoglein 1 and desmoglein 3 and studied the involvement of desmoglein 1 and desmoglein 3 in desmosome formation. During low-level expression of desmoglein 3DeltaEC in transduced HaCaT cells, keratin insertion at cell-cell contact sites was only partially inhibited and desmoplakin was partially stained at cell-cell contact sites. Low-level expression of desmoglein 1DeltaEC, however, resulted in complete inhibition of keratin insertion at the cell-cell contact sites, and desmoplakin was stained in perinuclear dots. These results indicate the dominant-negative effect of desmoglein 1DeltaEC on desmosome formation was stronger than that of desmoglein 3DeltaEC. Desmoglein 1DeltaEC coprecipitated plakoglobin to approximately the same extent as desmoglein 3DeltaEC. Therefore, we conclude that the dominant-negative effect of desmoglein 1DeltaEC is not simply due to plakoglobin sequestration. On the other hand, during low-level expression of full-length desmoglein 3 and desmoglein 1, they both colocalized with desmoplakin. During high-level expression, however, keratin insertion at cell-cell contact sites was inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at cell-cell contact sites in desmoglein 3 but not in desmoglein 1. These data suggest desmoglein 1 and desmoglein 3 expressed at low level were incorporated into desmosome but at high-level expression, desmoglein 1 disrupted desmosomes but desmoglein 3 did not. Our findings provide biologic evidence that desmoglein 1 and desmoglein 3 play a different functional role in cell-cell adhesion of keratinocytes.

    The Journal of investigative dermatology 2002;119;6;1231-6

  • Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome.

    Hanakawa Y, Schechter NM, Lin C, Garza L, Li H, Yamaguchi T, Fudaba Y, Nishifuji K, Sugai M, Amagai M and Stanley JR

    Department of Dermatology, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

    Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis.

    The Journal of clinical investigation 2002;110;1;53-60

  • Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus.

    Martel P, Gilbert D, Busson M, Loiseau P, Lepage V, Drouot L, Delaporte E, Prost C, Joly P, Charron D and Tron F

    INSERM U519, Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFR23), Faculté de Médecine et Hôpital Charles Nicolle, Rouen, France. philippe.martel@libertysurf.fr

    Pemphigus foliaceus (PF) is a rare and severe cutaneous autoimmune disease caused by autoantibodies directed against desmoglein 1 (DSG1), a desmosomal adhesion glycoprotein. We previously showed that the DSG1 gene is polymorphic and that a coding synonymous T/C single nucleotide polymorphism at position 809 is associated with PF. To determine whether the disease occurred as a consequence of complex genetic interactions, we simultaneously examined the contribution of major histocompatibility complex (MHC) class II and DSG1 polymorphisms to PF susceptibility. Our analysis performed in 31 PF patients and 84 healthy controls first confirmed the previously reported common DRB1*04 and DRB1*14 genetic background in PF and individualized DRB1*0102, DRB1*0402 and DRB1*0406, and DRB1*1404 as susceptibility MHC class II alleles in French Caucasian PF patients. It also showed that the C/C(809) genotype was associated with PF. Combined analysis of HLA class II and DSG1 polymorphisms with several distinct statistical methods including logistic regression, showed that the DRB1*04 allele and the C/C(809) genotype interact to confer a higher susceptibility to PF. These data demonstrate the role of epistasis between individual genes in PF susceptibility and illustrate the genetic complexity of organ-specific autoimmune diseases.

    Genes and immunity 2002;3;4;205-10

  • Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling.

    Chen X, Bonne S, Hatzfeld M, van Roy F and Green KJ

    Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.

    Plakophilins are a subfamily of p120-related arm-repeat proteins that can be found in both desmosomes and the nucleus. Among the three known plakophilin members, plakophilin 1 has been linked to a genetic skin disorder and shown to play important roles in desmosome assembly and organization. However, little is known about the binding partners and functions of the most widely expressed member, plakophilin 2. To better understand the cellular functions of plakophilin 2, we have examined its protein interactions with other junctional molecules using co-immunoprecipitation and yeast two-hybrid assays. Here we show that plakophilin 2 can interact directly with several desmosomal components, including desmoplakin, plakoglobin, desmoglein 1 and 2, and desmocollin 1a and 2a. The head domain of plakophilin 2 is critical for most of these interactions and is sufficient to direct plakophilin 2 to cell borders. In addition, plakophilin 2 is less efficient than plakophilin 1 in localizing to the nucleus and enhancing the recruitment of excess desmoplakin to cell borders in transiently transfected COS cells. Furthermore, plakophilin 2 is able to associate with beta-catenin through its head domain, and the expression of plakophilin 2 in SW480 cells up-regulates the endogenous beta-catenin/T cell factor-signaling activity. This up-regulation by plakophilin 2 is abolished by ectopic expression of E-cadherin, suggesting that these proteins compete for the same pool of signaling active beta-catenin. Our results demonstrate that plakophilin 2 interacts with a broader repertoire of desmosomal components than plakophilin 1 and provide new insight into the possible roles of plakophilin 2 in regulating the signaling activity of beta-catenin.

    Funded by: NIAMS NIH HHS: AR41836, R01 AR43380; NIDCR NIH HHS: P01 DE12328

    The Journal of biological chemistry 2002;277;12;10512-22

  • Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development.

    Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K and Herlyn M

    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania, PA 19104, USA.

    During melanoma development, transformed cells evade keratinocyte-mediated control by downregulating cell adhesion molecules. This study investigated the regulation of cell adhesion by hepatocyte growth factor (HGF) in melanoma. Melanocytes and two melanoma lines, WM164 and WM35, expressed normal level E-cadherin and Desmoglein 1, whereas most melanomas (18 out of 20) expressed no E-cadherin and significantly reduced Desmoglein 1. Overexpression of dominant negative E-cadherin and Desmoglein in melanocytes demonstrated that both molecules contribute to adhesion between melanocytes and keratinocytes. In contrast to melanocytes, most melanomas expressed HGF. All melanocytic cells expressed the HGF receptor c-Met, and autocrine HGF caused constitutive activation of c-Met, MAPK and PI3K. When autocrine activation was induced with HGF-expressing adenovirus, E-cadherin and Desmoglein 1 were decreased in melanocytes, WM164 and WM35. MAPK inhibitor PD98059 and PI3K inhibitor wortmannin partially blocked the downregulation, suggesting that both pathways are involved in this process. c-Met was coimmunoprecipitated with E-cadherin, Desmoglein 1 and Plakoglobin, suggesting that they form a complex (es) that acts to regulate intercellular adhesion. Together, the results indicate that autocrine HGF decouples melanomas from keratinocytes by downregulating E-cadherin and Desmoglein 1, therefore frees melanoma cells from the control by keratinocytes and allows dissemination of the tumor mass.

    Funded by: NCI NIH HHS: CA-10815, CA-25874, CA-47159, CA-76674, CA-80999

    Oncogene 2001;20;56;8125-35

  • A polymorphic variant of the gene coding desmoglein 1, the target autoantigen of pemphigus foliaceus, is associated with the disease.

    Martel P, Gilbert D, Drouot L, Prost C, Raux G, Delaporte E, Joly P and Tron F

    INSERM U519, Institut Fédératif de Recherche Multidisciplinaire sur les Peptides, Faculté de Médecine et H pital Charles Nicolle, Rouen, France.

    Two polymorphic markers were identified on the desmoglein 1 gene which encodes the autoantigen targeted by pathogenic antibodies in pemphigus foliaceus (PF), a cutaneous autoimmune blistering disease. The first marker, made of a variant haplotype of five mis-sense mutations located on the part of the gene encoding the fourth and fifth extracellular domains of the protein, is not associated with the disease. The second marker consists of a single silent T to C transition at position 809 and was found to be significantly more frequent (P = 0.015) in Caucasian PF patients (n = 36) than in controls (n = 98). Thus, pemphigus foliaceus constitutes another example of autoimmune disease in which the autoantigen polymorphism contributes to disease susceptibility.

    Genes and immunity 2001;2;1;41-3

  • N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma.

    Rickman L, Simrak D, Stevens HP, Hunt DM, King IA, Bryant SP, Eady RA, Leigh IM, Arnemann J, Magee AI, Kelsell DP and Buxton RS

    Division of Membrane Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.

    The N-terminal extracellular domain of the cadherins, calcium-dependent cell adhesion molecules, has been shown by X-ray crystallography to be involved in two types of interaction: lateral strand dimers and adhesive dimers. Here we describe the first human mutation in a cadherin present in desmosome cell junctions that removes a portion of this highly conserved first extracellular domain. The mutation, in the DSG1 gene coding for a desmoglein (Dsg1), results in the deletion of the first and much of the second beta-strand of the first cadherin repeat and part of the first Ca2+-binding site, and would be expected to compromise strand dimer formation. It causes a dominantly inherited skin disease, striate palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which affected individuals have marked hyperkeratotic bands on the palms and soles. In a three generation Dutch family with SPPK, we have found a G-->A transition in the 3" splice acceptor site of intron 2 of the DSG1 gene which segregated with the disease phenotype. This causes 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 emphasizes the importance of this part of the molecule for cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal function.

    Funded by: Wellcome Trust

    Human molecular genetics 1999;8;6;971-6

  • Defining the interactions between intermediate filaments and desmosomes.

    Smith EA and Fuchs E

    Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois 60637, USA.

    Desmoplakin (DP), plakoglobin (PG), and plakophilin 1 (PP1) are desmosomal components lacking a transmembrane domain, thus making them candidate linker proteins for connecting intermediate filaments and desmosomes. Using deletion and site-directed mutagenesis, we show that remarkably, removal of approximately 1% of DP's sequence obliterates its ability to associate with desmosomes. Conversely, when linked to a foreign protein, as few as 86 NH2-terminal DP residues are sufficient to target to desmosomes efficiently. In in vitro overlay assays, the DP head specifically associates with itself and with desmocollin 1a (Dsc1a). In similar overlay assays, PP1 binds to DP and Dsc1a, and to a lesser extent, desmoglein 1 (Dsg1), while PG binds to Dsg1 and more weakly to Dsc1a and DP. Interestingly, like DP, PG and PP1 associate with epidermal keratins, although PG is considerably weaker in its ability to do so. As judged by overlay assays, the amino terminal head domain of type II keratins appears to have a special importance in establishing these connections. Taken together, our findings provide new insights into the complexities of the links between desmosomes and intermediate filaments (IFs). Our results suggest a model whereby at desmosome sites within dividing epidermal cells, DP and PG anchor to desmosomal cadherins and to each other, forming an ordered array of nontransmembrane proteins that then bind to keratin IFs. As epidermal cells differentiate, PP1 is added as a molecular reinforcement to the plaque, enhancing anchorage to IFs and accounting at least partially for the increase in numbers and stability of desmosomes in suprabasal cells.

    The Journal of cell biology 1998;141;5;1229-41

  • Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion.

    Marcozzi C, Burdett ID, Buxton RS and Magee AI

    Division of Membrane Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

    Desmosomes are unique intercellular junctions in that they invariably contain two types of transmembrane cadherin molecule, desmocollins and desmogleins. In addition they possess a distinct cytoplasmic plaque structure containing a few major proteins including desmoplakins and the armadillo family member plakoglobin. Desmosomal cadherins are putative cell-cell adhesion molecules and we have tested their adhesive capacity using a transfection approach in mouse L cells. We find that L cells expressing either one or both of the desmosomal cadherins desmocollin 2a or desmoglein 1 display weak cell-cell adhesion activity that is Ca2+-dependent. Both homophilic and heterophilic adhesion could be detected. However, co-expression of plakoglobin with both desmosomal cadherins, but not with desmoglein 1 alone, resulted in a dramatic potentiation of cell-cell aggregation and the accumulation of detergent-insoluble desmosomal proteins at points of cell-cell contact. The effect of plakoglobin seems to be due directly to its interaction with the desmosomal cadherins rather than to its signalling function. The data suggest that the desmosome may obligatorily contain two cadherins and is consistent with a model in which desmocollins and desmogleins may form side by side heterodimers in contrast to the classical cadherins that are homodimeric. Plakoglobin may function by potentiating dimer formation, accretion of dimers to cell-cell contact sites or desmosomal cadherin stability.

    Funded by: Wellcome Trust

    Journal of cell science 1998;111 ( Pt 4);495-509

  • Characterization of the regulatory regions in the human desmoglein genes encoding the pemphigus foliaceous and pemphigus vulgaris antigens.

    Adams MJ, Reichel MB, King IA, Marsden MD, Greenwood MD, Thirlwell H, Arnemann J, Buxton RS and Ali RR

    Division of Membrane Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.

    The adhesive proteins in the desmosome type of cell junction consist of two members of the cadherin superfamily, the desmogleins and desmocollins. Both desmogleins and desmocollins occur as at least three different isoforms with various patterns of expression. The molecular mechanisms controlling the differential expression of the desmosomal cadherin isoforms are not yet known. We have begun an investigation of desmoglein gene expression by cloning and analysing the promoters of the human genes coding for the type 1 and type 3 desmogleins (DSG1 and DSG3). The type 1 isoform is restricted to the suprabasal layers of the epidermis and is the autoantigen in the autoimmune blistering skin disease pemphigus foliaceous. The type 3 desmoglein isoform is also expressed in the epidermis, but in lower layers than the type 1 isoform, and is the autoantigen in pemphigus vulgaris. Phage lambda genomic clones were obtained containing 4.2 kb upstream of the translation start site of DSG1 and 517 bp upstream of the DSG3 start site. Sequencing of 660 bp upstream of DSG1 and 517 bp upstream of DSG3 revealed that there was no obvious TATA box, but a possible CAAT box was present at -238 in DSG1 and at -193 in DSG3 relative to the translation start site. Primer extension analysis and RNase protection experiments revealed four putative transcription initiation sites for DSG1 at positions -163, -151, -148 and -141, and seven closely linked sites for DSG3, the longest being at -140 relative to the translation start site. The sequences at these possible sites at -166 to -159 in DSG1 (TTCAGTCC) and at -124 to -117 in DSG3 (CTTAGACT) have some similarity to the initiator sequence (CTCANTCT) described for a TATA-less promoter often from -3 to +5, and the true transcription initiator site might therefore be the A residue in these sequences. There were two regions of similarity between the DSG1 and DSG3 promoters just upstream of the transcription initiation sites, of 20 and 13 bp, separated by 41 bp in DSG1 and 36 bp in DSG3. The significance of these regions of similarity remains to be elucidated, but the results suggest that they represent a point at which these two desmoglein genes are co-ordinately regulated. Analysis of the upstream sequences revealed GC-rich regions and consensus binding sites for transcription factors including AP-1 and AP-2. Exon boundaries were conserved compared with the classical cadherin E-cadherin, but the equivalent of the second cadherin intron was lacking. A 4.2 kb region of the human DSG1 promoter sequence was linked to the lacZ gene reporter gene in such a way that there was only one translation start site, and this construct was used to generate transgenic mice. We present the first transgenic analysis of a promoter region taken from a desmosomal cadherin gene. Our results suggest that the 4.2 kb upstream region of DSG1 does not contain all the regulatory elements necessary for correct expression of this gene but might have elements that regulate activity during hair growth.

    The Biochemical journal 1998;329 ( Pt 1);165-74

  • Plakoglobin binding by human Dsg3 (pemphigus vulgaris antigen) in keratinocytes requires the cadherin-like intracytoplasmic segment.

    Roh JY and Stanley JR

    Dermatology Branch, National Institutes of Health, Bethesda, Maryland, USA.

    Desmogleins are transmembrane desmosomal cadherins. Two desmogleins, Dsg3 and Dsg1, have been shown to bind plakoglobin, an intracytoplasmic (IC) desmosomal plaque protein. This binding may be critical for desmosome assembly or stability. The IC domain of desmogleins consists of subdomains that are either desmoglein specific or homologous with the IC region of classical cadherins. Here we identify the domains of human Dsg3 that are critical for plakoglobin binding in human keratinocytes. We constructed eukaryotic expression vectors containing chimeric cDNAs that encode the extracellular domain of mouse E-cadherin (Ecad) with the transmembrane and IC domains of Dsg3, with increasing truncations eliminating various IC subdomains from the carboxy-terminus. These constructs were used for transient transfection of HaCaT cells. Extracts were subjected to immunoprecipition with an anti-mouse Ecad antibody (that does not precipitate human Ecad), thus precipitating the chimeric protein and any tightly associated plakoglobin. Co-precipitation of plakoglobin was confirmed by immunoblotting. These data show that the desmoglein-specific IC subdomains are not necessary for plakoglobin binding, but the carboxy-terminal 87 amino acids of the IC-cadherin-like segment subdomain are critical. Finally, we confirmed these results outside cells with in vitro transcription and translation, which also demonstrates that the Dsg3-plakoglobin interaction is direct and does not depend on other cellular factors. These results underscore the importance of a region, highly conserved in all desmogleins, in the carboxy terminus of the IC-cadherin-like subdomain for the localization of plakoglobin to desmosomes.

    The Journal of investigative dermatology 1995;104;5;720-4

  • Tandem arrangement of the closely linked desmoglein genes on human chromosome 18.

    Simrak D, Cowley CM, Buxton RS and Arnemann J

    Institut für Humangenetik, Universitätsklinik, Frankfurt/M., Germany.

    The desmogleins, together with the desmocollins, both members of the cadherin superfamily, are the adhesive proteins of the desmosome type of cell junction, characteristically found in epithelial cells. Three different human desmoglein isoforms are encoded by separate genes (DSG1, DSG2, and DSG3) located on chromosome 18q12.1. DSG2 has been shown to be the most widely expressed in all desmosome-containing tissues, whereas DSG1 and DSG3 are expressed only in certain tissues, mostly stratified squamous epithelia. 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. Yeast artificial chromosome clones carrying all three known human desmoglein genes have now been isolated. The smallest clone containing all three DSG genes was 275 kb, and the three desmoglein genes were clustered within a region of less than 150 kb. From the types of clone obtained and from restriction enzyme analysis the order of the DSG genes and their orientation was deduced to be 5'-DSG1-DSG3-DSG2-3'. There thus appears to be some correspondence between the order of DSG genes and their expression within tissues, raising the intriguing possibility that the organization of the desmoglein gene cluster is required for properly regulated gene expression.

    Genomics 1995;25;2;591-4

  • Posttranslational regulation of plakoglobin expression. Influence of the desmosomal cadherins on plakoglobin metabolic stability.

    Kowalczyk AP, Palka HL, Luu HH, Nilles LA, Anderson JE, Wheelock MJ and Green KJ

    Northwestern University Medical School, Department of Pathology, Chicago, Illinois 60611.

    Desmosomes are adhesive intercellular junctions that act as cell surface attachment sites for intermediate filaments. The desmosomal glycoproteins, desmogleins and desmocollins, are members of the cadherin family of adhesion molecules. In addition, desmoglein has been shown to coimmunoprecipitate with the junctional protein plakoglobin. To characterize further the interaction between plakoglobin and the desmosomal cadherins, stable mouse fibroblast (L-cells) cell lines were generated that express plakoglobin, desmoglein and plakoglobin, or desmocollin and plakoglobin. L-cell lines transfected with a plasmid encoding human plakoglobin expressed plakoglobin mRNA but very little plakoglobin protein. However, plakoglobin protein was expressed at high levels in L-cells coexpressing either desmoglein or desmocollin. In addition, both desmocollin and desmoglein were found to coimmunoprecipitate with plakoglobin. The transient expression of desmoglein in L-cell lines expressing plakoglobin mRNA resulted in the formation of a complex between plakoglobin and desmoglein and in the accumulation of plakoglobin protein. Furthermore, the rate of plakoglobin protein degradation was decreased by 15-20-fold in cell lines expressing either desmoglein or desmocollin. These results demonstrate that the desmosomal cadherins posttranslationally regulate plakoglobin expression by decreasing the rate of plakoglobin degradation.

    Funded by: NIAMS NIH HHS: AR41836

    The Journal of biological chemistry 1994;269;49;31214-23

  • The human genes for desmogleins (DSG1 and DSG3) are located in a small region on chromosome 18q12.

    Wang Y, Amagai M, Minoshima S, Sakai K, Green KJ, Nishikawa T and Shimizu N

    Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.

    Desmoglein is a transmembrane glycoprotein component of desmosomes in vertebrate epithelial cells. Two of the three currently known desmogleins are the autoantigens of autoimmune skin blistering diseases, pemphigus vulgaris and pemphigus foliaceus, in which autoantibodies cause the loss of cell adhesion of keratinocytes with resultant blister formation. In this study, the genes for two autoantigens (DSG1 for pemphigus foliaceus and DSG3 for pemphigus vulgaris) were mapped on band q12 of human chromosome 18 by fluorescence in situ hybridization. Furthermore, both genes were localized on a 320-kb genomic fragment separated by pulsed-field gel electrophoresis. These results suggest the possibility of a cluster for the desmoglein gene family on chromosome 18.

    Genomics 1994;20;3;492-5

  • Identification of the ubiquitous human desmoglein, Dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins.

    Schäfer S, Koch PJ and Franke WW

    Division of Cell Biology, German Cancer Research Center, Heidelberg.

    Desmosomes are junctions between epithelial, myocardiac, and certain other kinds of cells. They represent plasma membrane domains enriched in specific transmembrane glycoproteins, notably desmoglein (Dsg) and desmocollin (Dsc), both of which have recently been identified as members of the larger family of Ca(2+)-dependent cell adhesion molecules, the cadherins. Previously described forms of desmoglein have been isolated as proteins and cloned as cDNAs from epidermis and related stratified epithelia but have not been detected in the majority of other desmosome-containing tissues and cell culture lines. Here we present the complete cDNA-derived amino acid (aa) sequence of a different desmoglein polypeptide, termed Dsg2 (1069 aa, mol wt 116,760) and its precursor molecule (1117 aa, mol wt 122,384), which occurs in all human and bovine desmosome-producing tissues, tumors, and cell lines examined, epithelial as well as nonepithelial ones. We conclude that Dsg2, the largest molecule in this protein family, is the fundamental desmoglein common to all desmosome-possessing tissues, including simple epithelia and myocardium, and many cell cultures. Furthermore, in several tissues and cell lines Dsg2 is the only Dsg isoform detected so far. By contrast, the epidermal isoforms Dsg1 and Dsg3 are restricted to certain specialized epithelia, mostly stratified squamous ones. The importance of the junction-specific cadherin Dsg2 in tissue formation and carcinogenesis as well as in the development of autoimmune diseases of the Pemphigus type is discussed. In addition, we propose to use Dsg2 as a general marker common to all epithelial cells and tumors and to use the specific pattern of occurrence of Dsg and Dsc isoforms as an additional criterion for cell typing in tumor diagnosis.

    Experimental cell research 1994;211;2;391-9

  • Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.

    Amagai M, Klaus-Kovtun V and Stanley JR

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

    Pemphigus vulgaris (PV) is a life-threatening skin disease in which autoantibodies against a keratinocyte cell surface 130 kd glycoprotein, PV antigen (PVA), cause loss of cell-cell adhesion, with resultant epidermal blisters. We used affinity-purified PV IgG to isolate cDNA, containing the entire coding sequence for PVA, from human keratinocyte expression libraries. Northern blot analysis indicated PV mRNA expression only in stratified squamous epithelia. The deduced amino acid sequence of PVA was unique but showed significant homology with members of the cadherin family of Ca(2+)-dependent cell adhesion molecules, most markedly to desmoglein I. These findings demonstrate that a novel epithelial cadherin is the target of autoantibodies in PV.

    Cell 1991;67;5;869-77

  • Structural analysis and expression of human desmoglein: a cadherin-like component of the desmosome.

    Nilles LA, Parry DA, Powers EE, Angst BD, Wagner RM and Green KJ

    Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611.

    Desmosomes are adhesive cell junctions found in great abundance in tissues that experience mechanical stress. The transmembrane desmosomal glycoproteins have been proposed to play a role in cell adhesion; desmoglein I (DGI) is a major member of this class of desmosomal molecules. However, evidence supporting a role for DGI in cell adhesion or in the plaque is lacking. In order to begin to understand DGI function we have identified human cDNA clones encoding the entire mature polypeptide of 1000 amino acids. Our data suggest that like the bovine DGI molecule human DGI is highly related to the calcium-dependent class of cell adhesion molecules known as cadherins. Four related extracellular domains located in the amino-terminal domain of the molecule contain putative calcium binding sites originally identified in the cadherins. The highest degree of similarity between human N-cadherin and human DGI, and likewise between bovine DGI and human DGI, is greatest in the most amino-terminal extracellular domain. This suggests a conserved functional role for the extracellular domains, perhaps in calcium-mediated cell adhesion. The cytoplasmic portion of the molecule contains a cadherin-like region and, like bovine DGI, a carboxy-terminal tail that is not present in the cadherins, comprising three additional domains. One of these contains a novel repeating motif of 29 +/- 1 residues, first identified in bovine DGI. Each of the highly homologous repeating units is likely to consist of two beta-strands and two turns with special characteristics. Five amino acids that are identical in bovine and human DGI lie in the second of the two predicted beta-strands, and intriguingly contain putative target sites for protein kinase C. On the basis of structural analysis, a model predicting the disposition of human DGI domains in the desmosome is proposed. Northern analysis suggests that unlike bovine epidermis, which expresses a single mRNA of reported size approximately 7.6 kb, human foreskin and cultured keratinocytes display a complex pattern with bands of approximately 7.2, 4.0 and 3.0 kb. Each of these cross-hybridizing mRNAs is coordinately expressed in normal human keratinocytes in response to long-term culture and increased calcium.

    Funded by: NICHD NIH HHS: HD24430

    Journal of cell science 1991;99 ( Pt 4);809-21

  • 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).

    Arnemann J, Spurr NK, Wheeler GN, Parker AE and Buxton RS

    Laboratory of Eukaryotic Molecular Genetics, National Institute for Medical Research, London, United Kingdom.

    We have established PCR assays for the genes coding for the major proteins of the desmosome type of cell junction, the desmosomal cadherins DGI (desmoglein) and DGII/III (desmocollins), and the plaque proteins DPI/II (desmoplakin) and DPIII (plakoglobin) and used them to test human-mouse and human-rat somatic cell hybrids with different contents of human chromosomes. From these data we were able to assign DGI to chromosome 18 (DSG), DGII/III to chromosome 9p (DSC), DPI/II to chromosome 6p21-ter(DSP), and DPIII to chromosome 7 (JUP).

    Genomics 1991;10;3;640-5

  • Desmosomal glycoprotein DGI, a component of intercellular desmosome junctions, is related to the cadherin family of cell adhesion molecules.

    Wheeler GN, Parker AE, Thomas CL, Ataliotis P, Poynter D, Arnemann J, Rutman AJ, Pidsley SC, Watt FM, Rees DA et al.

    National Institute for Medical Research, Mill Hill, London, United Kingdom.

    Among the variety of specialized intercellular junctions, those of the adherens type have the most obvious association with cytoskeletal elements. This may be with the actin microfilament system as in the zonula adherens or with intermediate filaments as in the macula adherens, or desmosome. In the former case, it is clear that transmembrane glycoproteins of the cadherin family are important adhesive components of the molecular assembly. We now show for desmosomes that a major glycoprotein component (desmosomal glycoprotein DGI) has extensive homology with the cadherins, defining an extended family, but also has unique features in its cytoplasmic domain that are likely to be relevant to the association with intermediate rather than actin filaments. A novel 282-residue extension contains repeats of approximately 29 amino acid residues predicted to have an antiparallel beta-sheet structure, followed by a glycine-rich sequence. As in the cadherins, the extracellular domain contains possible Ca2(+)-binding sequences and a potential protease processing site. The cell adhesion recognition region (His-Ala-Val) of the cadherins is modified to Arg-Ala-Leu.

    Proceedings of the National Academy of Sciences of the United States of America 1991;88;11;4796-800

  • [Characterization of the desmoglein in renal cells in culture].

    Martínez RD

    Subdivisión de Medicina experimental Facultad de Medicina, Universidad Nacional Autónoma de México.

    Desmosome junctions are found in epithelial tissues. They both link cells externally and anchor cytoplasmic intermediate filaments to the plasma membrane. Quantitative and qualitative abnormalities in intercellular junctions have been described in a broad spectrum of human and animal cancers. Current efforts are aimed at exploring the possibility that some of these defects may account for the hallmarks of malignancy, namely tumour invasion and metastasis. Desmosomes are constituted by several proteins, one of them is desmoglein-1 (DG-1), a transmembrane glycoprotein who glycosylated portion is major component of the adhesion mediating desmoglia. In order to know the similarity between tissue DG-1 and cultured renal cells DG-1 was used antisera raised against DG-1 to identify cross-reacting components. Anti DG-1 antibodies stained cell-cell boundaries in a punctate fashion in epithelial tissue and on densely grown monolayers of renal cells. Radioimmunoprecipitation and immunoelectrotransference show positive reaction with anti DG-1 antibodies with desmosomes obtained from epithelial tissue and renal cells monolayers, but last one was less positive. Results suggest some minor differences between DG-1 extracted from diverse sources but they have a commun immunodominant epitope.

    Revista alergia Mexico 1991;38;2;59-64

Gene lists (3)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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