The expanded desmoglein gene family: The role of desmogleins in skin disorders

Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins. We have identified novel members of this family in both mouse and human. We describe cloning and characterization of three novel mouse genes Dsg4, Dsg1β, and Dsg1γ and a novel human desmoglein gene DSG4.; The essential role of desmoglein 4 in the skin was established by identifying mutations in two families with a novel inherited form of hypotrichosis, named Localized Autosomal recessive Hypotrichosis (LAH). We identified a homozygous intragenic 5 kb in-frame deletion in the affected members in both families designated EX5_8del. Furthermore, we describe two alleles of the lanceolate hair mouse, lah/lah and lahJ/lahJ , with mutations in the mouse Dsg4. We identified a homozygous null mutation in lahJ/lahJ mouse, designated 746insT, and a homozygous missense mutation in lah/lah mice, designated Y196S. Characterization of the phenotype of these naturally-occurring null and knock-in mutant mice revealed disruption of desmosomal adhesion, and perturbations in differentiation and proliferation in both epidermal and hair follicle keratinocytes. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.; Surprisingly, Dsg1β and Dsg1γ were found only in the mouse genome. Their high homology to the previously described mouse Dsg1 gene (now designated Dsg1α) justifies their designation as novel members of Dsg1 gene family. While expression of Dsg1α and Dsg1 β is mostly restricted to the skin, Dsg1γ was found to have a wider tissue distribution.; In addition to characterization of the new desmoglein genes and identification of mutations in desmoglein 4, we also identified a novel mutation in the DSG1 gene in a family with striate palmoplantar keratoderma, extending our knowledge on the role of desmosomal genes in human disease.