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.

Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients

“…In our study cohort, there is no evidence that FLG mutations have an effect on CER composition and lipid organization. In contrast, in a recent study in ichtyosis vulgaris patients ( 68 ), changes in the lamellar organization were observed between the patients and controls. In that investigation, however, the majority of the patients were homozygote or compound heterozygote with respect to FLG mutations, and no infl ammation was observed in these patients.…”

Epidermal tight junctions in health and disease

“…In addition, barrier function for lanthanum is abolished. 102 Interestingly, this study was performed in IV subjects without any clinical signs of inflammation, arguing that the TJ dysfunction is a direct effect of reduced/absent FLG. In the flaky tail mouse, which has a spontaneous mutation in FLG (similar to the mutations found in subjects with IV) and a matted tail mutation (Tmem79/matt) investigators have observed a reduction in occludin (at both mRNA and protein level).…”

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…51 For example, in IV (FLG) a pronounced decrease in keratohyaline granules is associated with abnormal LB secretion and lamellar/non-lamellar phase separation (Figure 1n), presumably due to altered enzyme activities. 39,52 XLI (STS) typically shows retained corneodesmosomes and phase separation of lipids in the stratum corneum interstices. 53 Harlequin ichthyosis (ABCA12) and CEDNIK (SNAP29) exhibit abnormal LBs 54 due to impaired lipid transport and abnormal intercellular lamellae in the stratum corneum.…”

“…material is subjected to a 'sodium dodecyl sulfate (SDS) heating test' , in which a lack of cross-linked cornified envelopes is substantiated by reduced integrity (Figures 1o-p) 39 (after boiling minced scales in a buffer-solution consisting of 2% SDS, ethylenediaminetetraacetic acid, dithiothreitol and Tris HCl for 10 min, and centrifuging, the corneocyte suspension is assessed by light microscopy in the Nomarsky mode). Unaffected cornified envelopes maintain integrity after boiling in SDS, as compared with TGM1-deficient material (Figure 1q).…”