TRANSGLUTAMINASES AND THEIR ROLE IN TNE PATHOGENESIS OF LAMELLAR ICHTHYOSIS AND ACRAL PEELING SKIN SYNDROME

The epidermis functions as a barrier against the environment by means of several layers of differentiated keratinocytes: the cornified envelope (CE). The resistance and insolubility of the CE is based on the formation of very stable bonds, catalysed by transglutaminases (TGs). TG1, TG3 and TG5 are involved in CE formation. Mutations in the TGM1 gene cause the congenital recessive skin disorder Lamellar Ichthyosis (LI). Generalized scaling and hyperkeratosis characterize lamellar Ichthyosis (LI). Other LI patients show a linkage to different regions, suggesting that LI is a genetically heterogeneous disorder. Recently, we have demonstrated that the abolition of TG5 activity in the skin, due to homozygosity for a missense mutation in TGM5, leads to an Acral form of Peeling Skin Syndrome (APSS). Peeling skin syndrome (PSS) is an autosomal recessive disease characterized by shedding of the outer epidermis. The general aim of this project is the understanding of the role of TGs in the pathogenesis of LI and APSS. We will generate animal models (TG3-/- and TG5-/- mice) to further study the molecular mechanism responsible for these diseases (TG1-/-, TG2-/- and TG1&TG2-/- mice are already available). This project will be carried out in collaboration with the IDI-IRCCS. IDI-IRCCS has an extremely wide patient population. The applicant will have access to large number of patients, as well as the clinical support for diagnosis.