Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders

Abstract

The genetic causes of most of the disorders of cornification have been uncovered. We now face the significant task of delineating how these mutations result in specific phenotypes. Because the permeability barrier resides in the extracellular lipid-enriched domains of the stratum corneum, it was anticipated that disorders of lipid metabolism would perturb the lamellar membrane structures of the extracellular domains and would result in a defective barrier. Unanticipated was the finding that inherited disorders of corneocyte proteins also exhibit, to varying degrees, an impaired permeability barrier. The effect of these corneocyte mutations on barrier function have shed light on how corneocytes interact with the intercellular lamellae to provide the barrier. In some entities, an impaired scaffold leads to fragmented and foreshortened lamellar membranes (e.g., transglutaminase-deficient lamellar ichthyosis, loricrin keratoderma). In others, there is impaired lamellar body secretion (e.g., epidermolytic hyperkeratosis) and altered lipid processing (e.g., Netherton syndrome), leading to deficiency of lamellar membrane structures. The combined insights from delineation of the pathogenesis of lipid metabolic defects and corneocyte protein abnormalities can be used to develop a function-driven model of disease pathogenesis. This model will aid in the development of more targeted approaches to therapy and in understanding some systemic complications of these disorders.

Figure 1. Key stratum corneum components

Figure 2. Lanthanum penetration through the extracellular pathway

In normal control skin (left panel), electron dense lanthanum tracer permeation is halted at the stratum granulosum – SC junction, whereas in ichthyosis vulgaris (right panel), tracer permeates beyond the junction, but remains restricted within the extracellular lamellar lipid pathway. Freshly obtained skin biopsies were exposed to 4% colloidal lanthanum nitrate tracer in 0.05 M Tris buffer, pH 7.4, for one hour, containing 2% glutaraldehyde and 2% paraformaldehyde, followed by post-fixation in OsO₄. Magnification bars = 1 µm (left panel), and = 2 µm (right panel).

Figure 3. Two compartment model of SC

In normal control skin (upper panel), the calcium ion gradient peaks in the lower SC, whereas after barrier disruption via solvent extraction of extracellular matrix lipids (lower panel) there is a rapid loss of the SC calcium gradient.

Figure 4. Scaffold abnormalities in lamellar ichthyosis and loricrin keratoderma

Figure 5. LB secretory defect in EHK

While the overall number of LB is normal in EHK, arrays of individual organelles remain restricted beneath the apical plasma membrane of outermost granular (SG) cells (A, B, arrowheads). C: Lack of LB secretion results in a paucity of extracellular deposits at the SG-SC interface (asterisks). RuO₄ post-fixation. Magnification bars = 0.5 µm.

Figure 6. Possible mechanisms for barrier abnormality in ichthyosis vulgaris

Figure 7. Pathogenesis of Netherton syndrome