Perspective: Mutations in Recessive Congenital Ichthyoses Illuminate the Origin and Functions of the Corneocyte Lipid Envelope.

The corneocyte lipid envelope (CLE), a monolayer of ϖ-hydroxyceramides, whose function(s) remain(s) uncertain, is absent in autosomal recessive congenital ichthyoses (ARCI) with mutations in enzymes that regulate epidermal lipid synthesis. Secreted lipids fail to transform into lamellar membranes in certain ARCI epidermis, suggesting the CLE provides a scaffold for the extracellular lamellae. But since cornified envelopes (CEs) are attenuated in these ARCI, the CLE may also provide a scaffold for subjacent CE formation, evidenced by restoration of CEs after CLE 'rescue.' We provide multiple lines of evidence that the CLE originates as lamellar body (LB) limiting membranes fuse with the plasma membrane: i) ABCA12 patients and Abca12-/- mice display normal CLEs; ii) CLEs are normal in Netherton syndrome, despite destruction of secreted LB contents; iii) CLEs are absent in VSP33B-negative patients; iv) limiting membranes of LBs are defective in lipid-synthetic ARCI; and v) lipoxygenases, lipase activity and LIPN co-localize within putative LBs.