Genetic Evidence for a Novel Human Desmosomal Cadherin, Desmoglein 4

Abstract

Desmosomes are essential adhesion structures in most epithelia that link the intermediate filament network of one cell to its neighbor, thereby forming a strong bond. The molecular components of desmosomes belong to the cadherin superfamily, the plakin family, and the armadillo repeat protein family. The desmosomal cadherins are calcium-dependent transmembrane adhesion molecules and comprise the desmogleins and desmocollins. To date, three human desmoglein isoforms have been characterized, namely desmogleins 1, 2, and 3 that are expressed in a tissue- and differentiation-specific manner. Here we have identified and characterized, at the genetic level, a novel human desmoglein cDNA sharing homology with desmogleins 1, 2, 3 and we name this desmoglein 4. The human desmoglein 4 cDNA (3.6 kb) contains an open reading frame of 3120 bp that encodes a precursor protein of 1040 amino acids. The predicted mature protein comprises 991 amino acids with a molecular weight of 107822 Da at pI 4.38. Human desmoglein 4 shares 41% identity with human desmoglein 1, 37% with human desmoglein 2, and 50% with human desmoglein 3. Analysis of the exon/intron organization of the human desmoglein 4 gene (DSG4) demonstrates that it is composed of 16 exons spanning approximately 37 kb of 18q12 and is situated between DSG1 and DSG3. We have demonstrated using RT-PCR on multiple tissue cDNA samples that desmoglein 4 has very specific tissue expression in salivary gland, testis, prostate, and skin.

Structural and Functional Diversity of Desmosomes

“…Whereas PKP1-3, PG, and DSP mapped to chromosomes 1, 12, 11, 17, and 6, respectively, all of the desmosomal cadherins were found in tandem on chromosome 18 at locus 18q12.1 (Wang et al, 1994;Simrak et al, 1995;Cowley et al, 1997aCowley et al, , 1997bBonne et al, 1998;Arnemann et al, 1991;Whittock & Bower, 2003). The curious arrangement of cadherin genes on chromosome 18 is grouped by cadherin type.…”

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

“…Among the desmosomal cadherins, desmoglein 2 and desmocollin 2 are the only proteins that are expressed ubiquitously in all desmosome-containing cells and tissues (Schä fer et al, 1994;Nuber et al, 1995), whereas the others have a unique tissue distribution. For example, desmoglein 4 expression was highest in the testis (Whittock and Bower, 2003), but little is known about its functional significance in spermatogenesis and fertility. It is noteworthy that both desmoglein-and desmocollin-specific peptides were needed to perturb desmosomal adhesion (Tselepis et al, 1998), illustrating that desmosomal cadherins favor heterotypic interactions to facilitate cell adhesion.…”

Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome

“…Until recently, 3 human and mouse desmogleins had been characterized, namely, Dsg1, Dsg2, and Dsg3, which are expressed in tissue-and differentiation-specific manners. Recent detailed genomic analyses identified a fourth member of the desmoglein family, Dsg4, in humans and mice (7,8). It has been elegantly demonstrated that mutations in the DSG4 gene cause inherited localized hypotrichosis in humans and the lanceolate hair phenotype in mice (7).…”

“…Therefore, anti-Dsg1 IgG autoantibodies alone are necessary and sufficient for blister formation in PF, and the Dsg4/ Dsg1-cross-reacting IgG autoantibodies play only a minor pathogenic role in blister formation in pemphigus. When the amino acid sequences of the desmoglein isoforms were compared, the overall protein identity of hDsg4 was higher with Dsg3 (50%) than with Dsg1 (41%) (8).…”

“…Dsg2 is expressed in all desmosomepossessing tissues, which include simple epithelia and the myocardium, while the expression of Dsg1 and Dsg3 is restricted to stratified squamous epithelium (6). Recently, a fourth member of the desmoglein family, Dsg4, was identified based on an analysis of the genomic structure of the desmosomal cadherin gene cluster on human chromosome 18q12 (7,8).…”