This process is particularly important in the terminal differentiation of the epidermis, where TGs heavily cross-link keratins and a range of differentiation-specific structural proteins, such as involucrin, loricrin, filaggrin, and small proline-rich proteins, in the formation of the cornified cell envelope in the biogenesis of the stratum corneum, the outermost, “dead” layer of the epidermis (Kalinin et al. 2002).
TGM5 mutations can cause acral peeling skin syndrome, an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis.
Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis.
Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity.
This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis.