title: 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.affiliation: Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Tzu-Kai
authors.initials: TK
authors.lastname: Lin
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Brandner
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hachem
authors.forename: Richard B
authors.initials: RB
authors.lastname: Presland
authors.forename: Philip
authors.initials: P
authors.lastname: Fleckman
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Aileen
authors.initials: A
authors.lastname: Sandilands
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Peter O
authors.initials: PO
authors.lastname: Fritsch
authors.forename: Michael
authors.initials: M
authors.lastname: Mildner
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002463:Cell Membrane Permeability / Q000235:genetics; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D005838:Genotype; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D015603:Keratinocytes / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins