Disease relevance of DSG1

• 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 [1].
• Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus [2].
• Dominant mutations in the DSG1 gene causing striate palmoplantar keratoderma result in hyperkeratosis of the skin on the parts of the body where pressure and abrasion are greatest, viz., on the palms and soles [3].
• Pemphigus foliaceus (PF) is a rare and severe cutaneous autoimmune disease caused by autoantibodies directed against desmoglein 1 (DSG1), a desmosomal adhesion glycoprotein [2].
• A mutation in DSG1 gene causes striate palmoplantar keratoderma and a mutation in DSG4 gene causes inherited hypotrichosis [4].

Psychiatry related information on DSG1

• Ganglioside GD3 (II3a(NeuAca2-8NeuAc)-LacCer, GD3) in reactive astrocytes from autopsied patients with Creutzfeldt-Jakob disease (CJD) and old cerebral infarction was investigated immunocytochemically, using mouse IgM anti-GD3 monoclonal antibody (DSG-1) [5].
• Particularly, a subtle structural difference around the DTG/DSG active site between the two structures has been observed that is useful for the in-depth selectivity study of BACE1 and BACE2 inhibitors, stimulating new therapeutic strategies for the treatment of Alzheimer's disease and Down syndrome as well [6].

High impact information on DSG1

• The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research [7].
• CONCLUSIONS: The prevalence of antibodies against desmoglein 1 is high among normal subjects living in an area among where fogo selvagem is endemic, and the onset of the disease is preceded by a sustained antibody response [7].
• By contrast, chimeras containing a Dsg tail, which accumulated in the plasma membrane, showed a dominant-negative effect: they not only were unable to form gap junction structures and plaques but also led to the disappearance of all endogenous desmosomes and the detachment of IFs from the plasma membrane [8].
• 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 [9].
• Recent evidence on the distribution of desmosomal glycoprotein isoforms that shows their combined expression in individual desmosomes has strengthened the belief that the latter are involved in epithelial differentiation and morphogenesis [10].

Chemical compound and disease context of DSG1

• 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 [11].
• CONCLUSIONS: The presence and localization in tumours of B-lymphocyte clones against proteins of the plakin family and desmoglein 3 in skin may not be confined to PNP with Castleman disease, but is possibly a common mechanism in PNP associated with various tumours [12].
• D-penicillamine-induced pemphigus foliaceus with autoantibodies to desmoglein-1 [13].
• This randomized, double-blind, placebo-controlled exploratory study examined the efficacy and safety of a low-dose oral contraceptive (Mircette), desogestrel/ethinyl estradiol [DSG/EE] and ethinyl estradiol [EE]) in relieving the symptoms of dysmenorrhea [14].
• Atropine (Atr), 0.02 mM, induced rapid detachment of cells from each other (acantholysis), and also increased phosphorylation of Dsg 3 by 33% [15].

Biological context of DSG1

• 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 [16].
• 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 [11].
• 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 [1].
• 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 [17].
• 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 [2].

Anatomical context of DSG1

• Epithelial cell membrane antigens other than DSG1 or DSG3 are targeted by effectors of PAMS autoimmunity [18].
• Desmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4) [11].
• So far, a unique isoform of Dsg1 has been described in humans, which includes several immunodominant T cell epitopes [11].
• Furthermore, in several tissues and cell lines Dsg2 is the only Dsg isoform detected so far [19].
• 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 [19].

Associations of DSG1 with chemical compounds

• Desmoglein is a transmembrane glycoprotein of the cadherin superfamily present in the desmosomal junction in vertebrate epithelial cells [20].
• To further understand the structure and assembly of the plakoglobin-cadherin complexes we analyzed amino acid residues involved in plakoglobin-Dsg interactions using alanine scanning mutagenesis [21].
• Of 42 serum samples (25 patients administered carbamazepine, eight patients administered valproic acid and nine healthy volunteers) tested by ELISA, three patients administered carbamazepine showed positive reactivity against both Dsg1 and Dsg3 [22].
• Results show distinct differences in the sedimentation profiles of these proteins, suggesting that they are not associated in the Triton X-100-soluble pool of proteins; this was also supported by the observation that DGI and DPI/II could not be coimmunoprecipitated in a complex with each other from sucrose gradient fractions [23].
• Interactions between the Triton X-100-soluble pools of DPI/II and DGI were analyzed by sedimentation of extracted proteins in sucrose gradients [23].

Physical interactions of DSG1

• The whole DSC/DSG gene complex occupies no more than about 700 kb, and the genes are arranged in the order cen-3'-DSC3-DSC2-DSC1-5'-5'-DSG1-DSG3-D SG2-3'-tel, so that the two gene clusters are transcribed outward from the interlocus region [24].
• In this study, we examined desmoglein (Dsg) 3 and other desmosomal molecules after pemphigus vulgaris (PV)-immunoglobulin G (IgG) binding to the Dsg3 on the cell surface in DJM-1 cells, a human squamous cell carcinoma cell line [25].
• Insertion of synaptophysin in the first three arm repeats selectively inactivates plakoglobin binding to desmoglein and desmocollin [26].
• Coexistence of pemphigus foliaceus and bullous pemphigoid. Demonstration of autoantibodies that bind to both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen [27].

Other interactions of DSG1

• Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion [28].
• 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 [11].
• Nevertheless, both plakoglobin and PKP1 are required for the formation of clustered structures containing DP and the Dsg1 tail that ultrastructurally appear similar to desmosomal plaques found in the epidermis [29].
• 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 [30].
• We describe the assembly of a cosmid and PAC contig of approximately 700 kb on human chromosome 18q12 spanning the DSC and DSG genes coding for the desmocollins and desmogleins [3].

Analytical, diagnostic and therapeutic context of DSG1

• In the autoimmune skin diseases pemphigus foliaceous and pemphigus vulgaris (PV), where the autoantigens are, respectively, encoded by the DSG1 and DSG3 genes, severe areas of acantholysis (cell separation), potentially life-threatening in the case of PV, are evident [3].
• 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 [19].
• To explain this apparent paradox, we examined the expression level of desmoglein (Dsg)3, pemphigus vulgaris antigen, and Dsg1, pemphigus foliaceus antigen, in human squamous mucosal epithelia and epidermis by immunofluorescence staining and immunoblotting [31].
• Immunoblotting was performed to compare Dsg1 and Dsg3 expression levels in extracts from epidermis and oral mucosa [31].
• We have screened two chromosome 18-specific cosmid libraries by hybridization with previously isolated YAC clones and DSC and DSG cDNAs, and a whole genome PAC library, both by hybridization with the YACs and by screening by PCR using cDNA sequences and YAC end sequence [3].

References