429 Defining a common mechanism that leads to scaling in Autosomal Recessive Congenital Ichthyoses

Hyperkeratosis defines the hyper proliferation of basal keratinocytes resulting in a buildup of corneocytes on the outer epidermis. It presents phenotypically as dry, flaky scales and is commonly associated with several diseases resulting from a defective skin barrier such as Eczema, Atopic dermatitis, Skin carcinoma, Psoriasis and the more severe Ichthyoses. Autosomal Recessive Congenital Ichthyosis (ARCI), is the umbrella term used to describe the heterogeneous group of keratinization disorders; lamellar ichthyosis, harlequin ichthyosis, and the congenital ichthyosiform erythroderma, all of which are non-syndromic and present with extensive scaling of the entire skin. Nine main genes have been identified whose mutations lead to the various forms of ARCI with the most common of these being mutations in Transglutaminase 1(Tgm1), Lipoxygenase-3 (AloxE3), 12(R)-lipoxygenase (Alox12b) and ATP-binding cassette sub-family A member 12(ABCA12). While the gene mutations that lead to ARCI are clear, the actual signalling mechanism that leads to scaling is poorle characterised. A better understanding of the molecular mechanisms that lead to scaling in Ichthyoses can better direct therapeutic interventions. We hypothesise that a common molecular mechanism leads to scaling in Ichthyoses and similar skin barrier defects, this pathway is responsible for ARCI with differing mutations presenting with a common phenotype. We provide evidence that the Toll-like receptor 1/2 (TLR1/2) signalling pathway activation is required for hyperkeratosis. Here, we additionally identify two transcription factors, Gata 3 and HoxA5 that are upregulated in hyperkeratosis and via activation of the TLR1/2 pathway.