174 Knock-down of SDR9C7 impairs epidermal barrier function

Abstract

The Mendelian Disorders of Cornification consist of a highly heterogeneous group of disorders, and the majority of non-syndromic cases belong to the family of autosomal recessive congenital ichthyosis (ARCI). Mutations in SDR9C7 have been associated with ACRI, and clinical manifestations include mild to moderately dry, scaly skin with or without hyperkeratosis, palmoplantar keratoderma, and erythroderma. SDR9C7, with short-chain dehydrogenase/reductase activity, is known as NAD- or NADP-dependent oxidoreductase and has been shown to be involved in the final step of epidermal lipid barrier formation by covalent binding of acylCer to the cornified envelope. Here, we present the clinical and molecular description of 19 ARCI patients in five consanguineous families with SDR9C7 mutations. We also downregulated the expression of SDR9C7 in keratinocytes by siRNA technique in 3D organotypic skin constructs. Our results demonstrated morphological and histological abnormalities in these constructs ex vivo, similar to those observed in ichthyosis patients. Moreover, the results from keratinocyte migration and epidermal dye penetration assays provided evidence for the role of SDR9C7 in the disease pathomechanism. Collectively, our results indicate that SDR9C7 deficiency by itself is sufficient to disrupt epidermal barrier function leading to ichthyotic phenotype.