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Journal of Lipid Research, Vol. 49, 697-714, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

Peter M. Elias^1,*,, Mary L. Williams, Walter M. Holleran^*,, Yan J. Jiang^*,,** and Matthias Schmuth^*,,**

^* Dermatology Services, Veterans Affairs Medical Center, University of California, San Francisco, CA
^** Medicine (Metabolism) Services, Veterans Affairs Medical Center, University of California, San Francisco, CA
Department of Dermatology, University of California, San Francisco, CA
Department of Pediatrics, University of California, San Francisco, CA

Published, JLR Papers in Press, February 2, 2008.

² An additional pathomechanism could also be operative in CHILD (for congenital hemidysplasia with ichthyosiform erythroderma and limb defects) and Conradi-Hünermann syndromes; that is, an accumulation of distal sterol precursors (7-dehydrocholesterol/zymosterol) could result in lamellar membranes that are deficient in cholesterol. Cholesterol is one of the key lipids (with Cers and free fatty acids) that are required to form mature lamellar membranes, and such cholesterol-deficient membranes provide a suboptimal barrier (Ref. 1; p. 74).

¹ To whom correspondence should be addressed. e-mail: eliasp{at}derm.ucsf.edu

One thing is certain. The sequencing of the genome will soon look like the easiest thing that biologists ever did. ...what the genes actually do—constitutes the real code of living systems. To crack that code will take centuries, but getting there will be more than half the fun. —Melvin Konner, "Weaving Life's Pattern," Nature 418: 279, 2002

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 (CSO₄) 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 CSO₄ 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 β-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.

Supplementary key words ATP binding cassette transporter 12 • arachidonate lipoxygenase • barrier function • epidermal lipids • harlequin ichthyosis • neutral lipid storage disease • recessive X-linked ichthyosis • stratum corneum • transepidermal water loss

Abbreviations: ALOX, arachidonate lipoxygenase; ARCI, autosomal recessive congenital ichthyosis; CDPX2, X-linked dominant chondrodysplasia punctata type 2; Cer, ceramide; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CIE, congenital ichthyosiform erythroderma; CSO₄, cholesterol sulfate; GD, Gaucher disease; HI, harlequin ichthyosis; KLK, kallikrein; LB, lamellar body; LI, lamellar ichthyosis; LOX, 12R-lipoxygenase; NLSDI, neutral lipid storage disease with ichthyosis; OMIM, Online Mendelian Inheritance in Man; PPAR, peroxisome proliferator-activated receptor; RCDP, rhizomelic chondrodysplasia punctata; RD, Refsum disease; RXLI, recessive X-linked ichthyosis; SSase, steroid sulfatase; SC, stratum corneum; SCCE, stratum corneum chymotryptic enzyme; SCTE, stratum corneum tryptic enzyme; SG, stratum granulosum; SLS, Sjögren-Larsson syndrome; TAG, triacylglyceride; TEWL, transepidermal water loss; TGM1, transglutaminase 1

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