Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth MPathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res 49:697-714

Dermatology Services, Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.
The Journal of Lipid Research (Impact Factor: 4.42). 05/2008; 49(4):697-714. DOI: 10.1194/jlr.R800002-JLR200
Source: PubMed


Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality "drives" pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of nonpolar lipid metabolism, triglyceride accumulation in neutral lipid storage disease as a result of a lipase mutation provokes a barrier abnormality via lamellar/nonlamellar phase separation within the extracellular matrix of the stratum corneum (SC). Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate (CSO(4)) accumulation also produces a permeability barrier defect through lamellar/nonlamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of CSO(4) as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (GD; from accumulation of glucosylceramides as a result of to beta-glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies (LBs) accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis (HI). The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation.

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    • "Unexpected Phenotypes in Slurp1-Deficient Mice and higher triglyceride levels were also found in the epidermis of several mal de Meleda patients (Kuster et al., 2003). The increased numbers of lipid droplets in the stratum corneum are likely due to impaired hydrolysis of triglycerides, a process that is essential for the formation of acylceramides and the epidermal water barrier (Elias et al., 2008). A similar accumulation of neutral lipid droplets in the stratum corneum is found in neutral lipid storage disease owing to CGI-58 deficiency (Demerjian et al., 2006), where triglyceride hydrolysis is clearly impaired (Radner et al., 2010; Ujihara et al., 2010; Radner et al., 2011). "
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    ABSTRACT: Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK.Journal of Investigative Dermatology advance online publication, 6 February 2014; doi:10.1038/jid.2014.19.
    Full-text · Article · Jan 2014 · Journal of Investigative Dermatology
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    • "Genetic anomalies in the complex physiological process of epidermal barrier formation result in scaly skin diseases (ichthyoses) with medical complications like dehydration, infections, chronic blistering, and rapidcalorie loss [17] [18] [19] [20]. Gene mutations implicated in the autosomal recessive congenital ichthyoses (ARCI) include ALOX12B, ALOX3, CYP4F22, ichthyin and TGM-1 [18,21–24]. "
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    ABSTRACT: This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3, and our current views on their functioning. In the outer epidermis, their consecutive actions oxidize linoleic acid esterified in ω-hydroxy-ceramide to a hepoxilin-related derivative. The relevant background to hepoxilin and trioxilin biochemistry is briefly reviewed. We outline the evidence that linoleate in the ceramide is the natural substrate of the two LOX enzymes and our proposal for its importance in construction of the epidermal water barrier. Our hypothesis is that the oxidation promotes hydrolysis of the oxidized linoleate moiety from the ceramide. The resulting free ω-hydroxyl of the ω-hydroxyceramide is covalently bound to proteins on the surface of the corneocytes to form the corneocyte lipid envelope, a key barrier component. Understanding the role of the LOX enzymes and their hepoxilin products should provide rational approaches to ameliorative therapy for a number of the congenital ichthyoses involving compromised barrier function. 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.
    Full-text · Article · Sep 2013 · Biochimica et Biophysica Acta
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    • "Currently, autosomal recessive congenital ichthyosis (ARCI) in humans is associated with mutations in genes including TGM1 (MIM*190195), ABCA12 (MIM *607800), ALOXE3 (MIM *607206), ALOX12B (MIM*603741), ABHD5 (MIM *604780), NIPAL4 (MIM *609383), CYP4F22 (MIM*611495), and SLC27A4/Fatp4 (MIM *604194) related to this study [38]. Among them, mutations in ABCA12, a member of the ABC transporter superfamily, cause Harlequin ichthyosis (HI), a disorder that presents at birth with a thick, tight skin that is susceptible to cracking [1]. In keratinocytes, ABCA12 is thought to regulate the transfer of glucosyl-ceramides into lamellar bodies. "
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    ABSTRACT: Congenital ichthyoses are life-threatening conditions in humans. We describe here the identification and molecular characterization of a novel recessive mutation in mice that results in newborn lethality with severe congenital lamellar ichthyosis. Mutant newborns have a taut, shiny, non-expandable epidermis that resembles cornified manifestations of autosomal-recessive congenital ichthyosis in humans. The skin is stretched so tightly that the newborn mice are immobilized. The genetic defect was mapped to a region near the proximal end of chromosome 2 by SNP analysis, suggesting Fatp4/Slc27a4 as a candidate gene. FATP4 mutations in humans cause ichthyosis prematurity syndrome (IPS), and mutations of Fatp4 in mice have previously been found to cause a phenotype that resembles human congenital ichthyoses. Characterization of the Fatp4 cDNA revealed a fusion of exon 8 to exon 10, with deletion of exon 9. Genomic sequencing identified an A to T mutation in the splice donor sequence at the 3'-end of exon 9. Loss of exon 9 results in a frame shift mutation upstream from the conserved very long-chain acyl-CoA synthase (VLACS) domain. Histological studies revealed that the mutant mice have defects in keratinocyte differentiation, along with hyperproliferation of the stratum basale of the epidermis, a hyperkeratotic stratum corneum, and reduced numbers of secondary hair follicles. Since Fatp4 protein is present primarily at the stratum granulosum and the stratum spinosum, the hyperproliferation and the alterations in hair follicle induction suggest that very long chain fatty acids, in addition to being required for normal cornification, may influence signals from the stratum corneum to the basal cells that help to orchestrate normal skin differentiation.
    Full-text · Article · Nov 2012 · PLoS ONE
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