Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

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

    Research output: Contribution to journalArticlepeer-review

    192 Citations (Scopus)


    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. (Am J Pathol 2011, 178:2252-2263; DOI: 10.1016/j.ajpath.2011.01.053)

    Original languageEnglish
    Pages (from-to)2252-2263
    Number of pages12
    JournalAmerican Journal of Pathology
    Issue number5
    Publication statusPublished - May 2011


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