MOLECULAR MECHANISMS INVOLVED IN THE PATHOGENESIS OF LAMELLAR ICHTHYOSIS: ROLE OF TRANSGLUTAMINASES

Lamellar Ichthyosis (LI) is a congenital recessive skin disorder characterized by generalized scaling and hyperkeratosis. Two groups have first described mutations in the transglutaminase (TGase) 1 gene as the cause of LI. However, it has also been shown that LI is a genetically heterogeneous disorder: beside chromosome 14q11, where TGase1 is located, linkage has also been described to chromosome regions 2q33-35, to chromosome 19 or to neither. Therefore, other genes must be involved in the disease, probably defects in other TGases or abnormalities in TGases substrates. The general aim of this project is to continue our studies on the molecular mechanisms responsible for LI, taking advantage of the TGase1 and TGase2 knock-out mice. TGase 1 knock-out mice are an excellent animal model for the disease. In addition we will continue to carry out the investigation on new genes involved in LI pathogenesis. This research line will be divided into the following specific aims: 1. Collection of families and linkage analysis (when possible); 2. Identification of new mutations and study of their biochemical alterations; 3. Analysis of the cornified envelope of TGase1-/-, TGase2-/- and TGase1&2-/- mice; 4. Studies on other novel TGases (i.e. TGase5) that could be involved in keratinization, LI pathogenesis or in compensation mechanisms; 5. Identification and characterization of TGases-modulating agents of potential therapeutic benefit for keratinization disorders using as model TGase1-/- mice. Although we focus on a rare genetic disease, the results expected will increase the general knowledge on the role of TGases in epidermal development and keratinization and their contribution to skin barrier function in vivo. Moreover, This study might provide a novel approach for therapeuthical treatments of LI patients by studing the molecular mechanisms of the pathogenesis and identifying new agents that are able to modulate TGases expression and/or activity.