Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

College of Pharmacy Chungbuk Natl University Cheongju South Korea

Department of BioCosmetics Seowon University Cheongju South Korea

Department of BioCosmetics Seowon University Cheongju South Korea; Department of Pharmacy Charles University Hradec Kralove Czech Republic

Department of Dermatopathology School of Veterinary Medicine University of Pennsylvania Philadelphia Pennsylvania

Department of Pathology Oslo University Hospital Oslo Norway

Department of Pharmacy Charles University Hradec Kralove Czech Republic

Department of Pharmacy Charles University Hradec Kralove Czech Republic; Department of Dermatology Genetics and Pathology Yale University New Haven Connecticut

Department of Research and Development cyberDERM Media Pennsylvania

Dermatology Service Veterans Affairs Medical Center San Francisco California; Department of Dermatology University of California San Francisco San Francisco California

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ω-O-Acylceramides but not ω-hydroxy ceramides are required for healthy lamellar phase architecture of skin barrier lipids

Effects of omega-O-acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models