Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.
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Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. / Gruber, Robert; Elias, Peter M; Crumrine, Debra; Lin, Tzu-Kai; Brandner, Johanna; Hachem, Jean-Pierre; Presland, Richard B; Fleckman, Philip; Janecke, Andreas R; Sandilands, Aileen; McLean, W H Irwin; Fritsch, Peter O; Mildner, Michael; Tschachler, Erwin; Schmuth, Matthias.
In: AM J PATHOL, Vol. 178, No. 5, 5, 2011, p. 2252-2263.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.
AU - Gruber, Robert
AU - Elias, Peter M
AU - Crumrine, Debra
AU - Lin, Tzu-Kai
AU - Brandner, Johanna
AU - Hachem, Jean-Pierre
AU - Presland, Richard B
AU - Fleckman, Philip
AU - Janecke, Andreas R
AU - Sandilands, Aileen
AU - McLean, W H Irwin
AU - Fritsch, Peter O
AU - Mildner, Michael
AU - Tschachler, Erwin
AU - Schmuth, Matthias
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Young Adult
KW - Genotype
KW - Mutation
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Microscopy, Electron, Transmission
KW - Cell Membrane Permeability/genetics
KW - Extracellular Matrix/pathology
KW - Ichthyosis Vulgaris/genetics/pathology/physiopathology
KW - Intermediate Filament Proteins/genetics
KW - Keratinocytes/pathology
KW - Skin/physiopathology
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Young Adult
KW - Genotype
KW - Mutation
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Microscopy, Electron, Transmission
KW - Cell Membrane Permeability/genetics
KW - Extracellular Matrix/pathology
KW - Ichthyosis Vulgaris/genetics/pathology/physiopathology
KW - Intermediate Filament Proteins/genetics
KW - Keratinocytes/pathology
KW - Skin/physiopathology
M3 - SCORING: Journal article
VL - 178
SP - 2252
EP - 2263
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 5
M1 - 5
ER -