Disease relevance of Dsg1a

• We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus [1].
• Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1 [2].
• Pemphigus is an autoimmune disease of skin adhesion associated with autoantibodies against a number of keratinocyte antigens, such as the adhesion molecules desmoglein (Dsg) 1 and 3 and acetylcholine receptors [3].
• We recently identified a novel desmoglein family member, Desmoglein 4 (Dsg4), using a positional cloning approach in two families with localized autosomal recessive hypotrichosis (LAH) and in the lanceolate hair (lah) mouse [4].
• Mutations in desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma [5].

High impact information on Dsg1a

• Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity [6].
• LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity [6].
• We show here that exfoliative toxin A cleaved mouse and human Dsg1, but not closely related cadherins such as Dsg3 [2].
• Conformational epitopes of antidesmoglein autoantibodies in pemphigus patients' sera and the specific cleavage site of desmoglein 1 by exfoliative toxin have been identified, implicating the N-terminal extracellular domains of the desmogleins as critical regions for controlling intercellular adhesion [7].
• Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1 [8].

Chemical compound and disease context of Dsg1a

• To address these questions we used transgenic mouse technology to produce an NH2-terminally truncated desmoglein (Pemphigus Vulgaris Antigen or Dsg3) in cells known to express its wild-type counterpart [9].
• Pemphigus foliaceus (PF) is a life-threatening autoimmune blistering skin disease caused by pathogenic IgG autoantibodies against desmoglein 1 (dg1), a desmosomal cadherin-type adhesion glycoprotein [10].
• Pemphigus foliaceus (PF) antigens, frequently together with desmoglein 1, involucrin and keratins specific for the upper layer of the epidermis, were expressed by stratified keratinocytes but not the cells in the monolayers [11].
• Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4alpha, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria [12].

Biological context of Dsg1a

• The desmoglein compensation hypothesis, namely that one desmoglein can compensate for loss of function of another, has been proposed to explain the tissue specificity of the autoantibody-induced loss of cell adhesion in pemphigus [13].
• Immunoblotting showed transgene expression in skin, and immunofluorescence showed desmoglein-1 in the telogen club of DSG3-/-TG+ but not DSG3-/-TG- mice [13].
• The Dsg1 gamma gene maps within the desmosomal gene cluster, between Dsc1 and Dsg1 alpha [14].
• However, we recently cloned two novel additional mouse Dsg1 genes, Dsg1-beta and -gamma, which flank the original Dsg1-alpha on chromosome 18 [15].
• Extensive sequencing of the human genome has revealed only one copy of the Dsg1 gene [15].

Anatomical context of Dsg1a

• In this study, we examined the different roles that Dsc and Dsg play in the formation of desmosomes, by using dominant-negative mutants [16].
• Expression of desmoglein 1 compensates for genetic loss of desmoglein 3 in keratinocyte adhesion [13].
• Currently, there are three known isoforms of Dsgs (Dsg1, Dsg2, and Dsg3), encoded by distinct genes that are differentially expressed to determine their tissue specificity and differentiation state of epithelial cells [17].
• RT-PCR using a multitissue cDNA panel demonstrated that while Dsg1-alpha mRNA was expressed in 15- to 17-day-old embryos and adult spleen and testis, Dsg1-beta mRNA was detected in 17-day-old embryos only [17].
• In the hair follicle, all Dsg1 isoforms were present throughout the entire process of its development and cycling but the expression of Dsg1 isoforms is subject to significant hair cycle-dependent changes [15].

Associations of Dsg1a with chemical compounds

• 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 [18].
• In this study, the molecular organization of complexes formed by plakoglobin and desmoglein 1, 2, or 3 are further examined through immunoprecipitation, size exclusion chromatography and sucrose density sedimentation analysis [19].
• Using an immunoblotting technique, we recently demonstrated that a subgroup of PF patients have autoantibodies to the desmosomal core glycoprotein, desmoglein I (DGI) [20].
• Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded skin samples by use of a biotinylated mouse monoclonal anti-Dsg 1 and 2 antibody raised against bovine muzzle [21].
• Considering colocalization the pattern of galectin-3-binding sites coincided with the presence of desmosomal proteins such as desmoplakin-1 and desmoglein but not beta(1) integrin, a potential ligand [22].

Other interactions of Dsg1a

• Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease that is caused by IgG autoantibodies against the cadherin-type adhesion molecule desmoglein (Dsg)3 [23].
• Novel member of the mouse desmoglein gene family: Dsg1-beta [17].
• In this study, we have cloned and characterized the mouse Dsg1 and Dsg2 genes [24].
• The expression of plakoglobin, desmoglein and E-cadherin at ED14 suggested that the main cell-cell junctional complexes were adherens junctions [25].
• Desmosomes were localized with antibodies against desmoglein, and hemidesmosomes using antibodies against BP-230 and HD-1 proteins [26].

Analytical, diagnostic and therapeutic context of Dsg1a

• ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1 [1].
• We demonstrate this specific cleavage in cell culture, in neonatal mouse skin and with recombinant Dsg1, and conclude that Dsg1 is the specific receptor for exfoliative toxin A cleavage [2].
• The anti-Dsg 1 antibody also was not required, as its presence in PV IgG does not alter the PV-like phenotype in skin organ cultures and because pemphigus foliaceus IgGs produce a distinct phenotype in Dsg3(null) mice [3].
• Genomic sequence analysis of the mouse desmoglein cluster reveals evidence for six distinct genes: characterization of mouse DSG4, DSG5, and DSG6 [27].
• We produced recombinant desmoglein-1 and desmoglein-3, and used them in highly sensitive and specific enzyme-linked immunosorbent assays, as well as immunoprecipitation assays [28].

References