Pathogenesis of the permeability barrier abnormality in epidermolytic hyperkeratosis

Matthias Schmuth, Gil Yosipovitch, Mary L. Williams, Florian Weber, Helmut Hintner, Susana Ortiz-Urda, Klemens Rappersberger, Debra Crumrine, Kenneth R. Feingold, Peter M. Elias

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


Epidermolytic hyperkeratosis is a dominantly inherited ichthyosis, frequently associated with mutations in keratin 1 or 10 that result in disruption of the keratin filament cytoskeleton leading to keratinocyte fragility. In addition to blistering and a severe disorder of cornification, patients typically display an abnormality in permeability barrier function. The nature and pathogenesis of the barrier abnormality in epidermolytic hyperkeratosis are unknown, however. We assessed here, first, baseline transepidermal water loss and barrier recovery kinetics in patients with epidermolytic hyperkeratosis. Whereas baseline transepidermal water loss rates were elevated by approximately 3-fold, recovery rates were faster in epidermolytic hyperkeratosis than in age-matched controls. Electron microscopy showed no defect in either the cornified envelope or the adjacent cornified-bound lipid envelope, i.e., a corneocyte scaffold abnormality does not explain the barrier abnormality. Using the water-soluble tracer, colloidal lanthanum, there was no evidence of tracer accumulation in corneocytes, despite the fragility of nucleated keratinocytes. Instead, tracer, which was excluded in normal skin, moved through the extracellular stratum corneum domains. Increasing intercellular permeability correlated with decreased quantities and defective organization of extracellular lamellar bilayers. The decreased lamellar material, in turn, could be attributed to incompletely secreted lamellar bodies within granular cells, demonstrable not only by several morphologic findings, but also by decreased delivery of a lamellar body content marker, acid lipase, to the stratum corneum inter-stices. Yet, after acute barrier disruption a rapid release of preformed lamellar body contents was observed together with increased organelle contents in the extracellular spaces, accounting for the accelerated recovery kinetics in epidermolytic hyperkeratosis. Accelerated recovery, in turn, correlated with a restoration in calcium in outer stratum granulosum cells in epidermolytic hyperkeratosis after barrier disruption. Thus, the baseline permeability barrier abnormality in epidermolytic hyperkeratosis can be attributed to abnormal lamellar body secretion, rather than to corneocyte fragility or an abnormal cornified envelope/cornified-bound lipid envelope scaffold, a defect that can be overcome by external applications of stimuli for barrier repair.

Original languageEnglish (US)
Pages (from-to)837-847
Number of pages11
JournalJournal of Investigative Dermatology
Issue number4
StatePublished - 2001
Externally publishedYes


  • Cornified envelope
  • Intermediate filaments
  • Keratin
  • Stratum corneum
  • Transepidermal water loss

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology


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