One remarkable molecule: filaggrin

Abstract

The discovery, in 2006, that loss-of-function mutations in the filaggrin (FLG) gene are the cause of ichthyosis vulgaris-the most common disorder of keratinization-and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG-null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation.

Figure 1

Historical perspective on filaggrin research Insert shows immunohistochemical staining of human epidermis, with filaggrin in green, basal-specific keratin 5 in red and nuclei stained blue.

Figure 2

Diagrammatic representation of FLG gene structure and sequencing strategy? FLG is a large gene located on chromosome 1q21, within the epidermal differentiation complex, a dense cluster of genes involved with keratinocyte terminal differentiation. The gene product is profilaggrin, an insoluble polyprotein which is proteolyzed to release functional filaggrin monomers. Full sequencing of the FLG gene is time-consuming and requires 10 or more PCR reactions and more than 30 sequencing reactions. UTR, untranslated region; bp, base pairs; PCR, polymerase chain reaction

Figure 3

Profilaggrin, filaggrin and their constituent amino acids are multifunctional proteins contributing to the formation and function of the skin barrier Diagram summarizing the known and possible functions of profilaggrin, filaggrin and amino acids released by filaggrin proteolysis.