Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.

Abstract

Although it is widely accepted that filaggrin (FLG) deficiency contributes to an abnormal barrier function in ichthyosis vulgaris and atopic dermatitis, the pathomechanism of how FLG deficiency provokes a barrier abnormality in humans is unknown. We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function. Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum. Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture. In addition, we observed reductions in corneodesmosome density and tight junction protein expression. Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix. These results clarify how FLG mutations impair epidermal permeability barrier function.

• Authors: Robert Gruber, Peter M Elias, Debra Crumrine, Tzu-Kai Lin, Johanna M Brandner, Jean-Pierre Hachem, Richard B Presland, Philip Fleckman, Andreas R Janecke, Aileen Sandilands, W H Irwin McLean, Peter O Fritsch, Michael Mildner, Erwin Tschachler, Matthias Schmuth
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 5 Pg. 2252-63 (May 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21514438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• FLG protein, human
• Filaggrin Proteins
• Intermediate Filament Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Cell Membrane Permeability (genetics)
• Extracellular Matrix (pathology)
• Female
• Filaggrin Proteins
• Genotype
• Humans
• Ichthyosis Vulgaris (genetics, pathology, physiopathology)
• Intermediate Filament Proteins (genetics)
• Keratinocytes (pathology)
• Male
• Microscopy, Electron, Transmission
• Middle Aged
• Mutation
• Reverse Transcriptase Polymerase Chain Reaction
• Skin (physiopathology)
• Young Adult