New keys for the pathophysiology of Peeling Skin Disease revealed by transcriptomic analysis of two Corneodesmosin-deficient mouse models
Sarra Zaafouri1, Mélanie Pichery1, Anne Huchenq-Champagne1, Fréderic Valentin2, Vinzenz Oji2, Juliette Mazereeuw-Hautier1,3, Guy Serre1, Nathalie Jonca1
1UDEAR, UMR 1056 Inserm-Université de Toulouse, France. 2Department of Dermatology, University Hospital Muenster, Germany. 3Centre de Référence des Maladies Rares de la Peau, Hôpital Larrey, CHU de Toulouse, France.
The Peeling Skin Disease (PSD; OMIM 270300) is a rare inflammatory ichthyosis characterized by lifelong patchy peeling of the skin associated with eczema, food allergy and severe itching. It is due to homozygous loss-of-function mutations in Corneodesmosin (CDSN), a gene coding an adhesive protein crucial for stratum corneum cohesion. Our aim is to dissect the still poorly known pathophysiological mechanisms of PSD. To this end, we analyzed cutaneous gene expression profiles using two epidermal-selective Cdsn-deficient mouse models representative of early (occurrence of the defect in permeability barrier in Cdsnep-/- E18.5 embryos) and chronic (permanent permeability defect in Cdsniep-/-adult mice) phases of the disease, respectively. Distinct molecular signatures related to skin barrier repair response were highlighted: increased expression of inflammatory and proliferative genes in Cdsnep-/- E18.5 vs antimicrobial defense and cornification genes in Cdsniep-/- adult mice. A strong expression of genes encoding cystatin A, an inhibitor of cysteine proteases, and several serine proteases of the kallikrein (Klk) family, was distinguishable in Cdsniep-/- mice and was secondarily confirmed in the skin of PSD patients. Among the Klks, Klk13/KLK13 was the most strongly up-regulated while Klk5/KLK5 was not induced at all. Thus Klk13/KLK13, whose epidermal function is largely unknown, could be involved in inflammatory response and dysregulated desquamation in PSD. In conclusion, our Cdsniep-/- adult mouse model seems especially relevant to decipher the pathophysiology of PSD and could be useful to further characterize the candidate genes identified. This work will help to improve knowledge of PSD and certainly other inflammatory skin diseases with epidermal barrier defects.

New keys for the pathophysiology of Peeling Skin Disease revealed by transcriptomic analyses of two Corneodesmosin-deficient mouse models