Analysis of cellular molecules associated with keratinocyte differentiation

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We studied peptidylarginine deiminases (PADs) expression in human epidermis (Cell Mol Life Sci 2005). We found that PAD1,2 and 3 are expressed. PAD1 and PAD3 are co-localized with filaggrin. PAD was present up to the supper corneocytes where it deiminates keratin K1.We have shown that LEKI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum in the epidermis (J Invest Dermatol 2005).We also disclosed that in Netherton syndrome where LEKTI is absent, an abnormal split was seen in the superficial stratum granulosum, suggesting that LEKTI is preventing premature loss of stratum corneum cohesion.We generated SPINK5-deficient mice as a model for Netherton syndrome. Using this model, we showed that desmosome cleavage due to desmoglein 1 degradation is the primary pathogenic event in this disease. (Nature Genetics 2005).We describe a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK syndrome) caused by a mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking (Am J Hum Genet 2005). In the ichthyotic patient skin, secretion of lamellar granule proteins was inhibited.We have identified novel members of lamellar granule proteins, namely A2ML (alpha-2 macroglobulin-like) and Dermokin (J Biol Chem, 2006,J Invest Dermatol 2006).