Role of cholesterol sulfate in epidermal structure and function: Lessons from X-linked ichthyosis

• X-linked ichthyosis (XLI) is due to loss-of-function mutations in steroid sulfatase (SSase; STS).
• Cholesterol sulfotransferase (SULT2B1b) generates CSO4, while SSase degrades CSO4 in the epidermis.
• Sulfation of cholesterol is linked to epidermal differentiation and corneocyte formation.
• The phenotype in XLI results from persistence of “pristine” corneodesmosomes in the outer SC.
• Disruption of lamellar bilayers creates a pathway for excess water loss in XLI.

X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome. Syndromic features are mild or unapparent unless contiguous genes are affected. In normal epidermis, cholesterol sulfate is generated by cholesterol sulfotransferase (SULT2B1b), but desulfated in the outer epidermis, together forming a ‘cholesterol sulfate cycle’ that potently regulates epidermal differentiation, barrier function and desquamation. In XLI, cholesterol sulfate levels my exceed 10% of total lipid mass (≈ 1% of total weight). Multiple cellular and biochemical processes contribute to the pathogenesis of the barrier abnormality and scaling phenotype in XLI. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.