Knockdown of SDR9C7 Impairs Epidermal Barrier Function.

The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal recessive congenital ichthyosis. Mutations in SDR9C7 have been associated with autosomal recessive congenital ichthyosis, and clinical manifestations include mild to moderately dry, scaly skin with or without hyperkeratosis, palmoplantar keratoderma, and erythroderma. SDR9C7, with short-chain dehydrogenase and/or reductase activity, is known as nicotinamide adenine dinucleotide‒ or nicotinamide adenine dinucleotide phosphate‒dependent oxidoreductase and has been shown to be involved in the final step of epidermal lipid barrier formation by covalent binding of acylceramide to the cornified envelope. In this study, we present the clinical and molecular description of 19 patients with autosomal recessive congenital ichthyosis in five consanguineous families with SDR9C7 mutations. We also downregulated the expression of SDR9C7 in keratinocytes using the small interfering RNA technique in three-dimensional organotypic skin constructs. Our results demonstrated morphological and histological abnormalities in these constructs ex vivo, similar to those observed in patients with ichthyosis. 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.