The Discovery and Function of Filaggrin

Abstract

Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.

Exome variants associated with asthma and allergy

“…It seems from this analysis, that the genetics of atopic dermatitis is clearly separated from allergic rhinitis and asthma. Atopic dermatitis is already sufficiently described by filaggrin mutations 20 which is in line with our earlier observation that atopic dermatitis is genetically a largely different disease 21 . Filaggrin mutations may act on top of an allergic predisposition while there are no further shared variants in this analysis.…”

Exon variants associated with asthma and allergy1

“…It seems from this analysis, that the genetics of atopic dermatitis is clearly separated from allergic rhinitis and asthma. Atopic dermatitis is already sufficiently described by filaggrin mutations (24) and in line with our early observation that atopic dermatitis is a genetically a largely different disease (25). Filaggrin mutations may act on top of an allergic predisposition while there have been no further shared variants in this analysis.…”

Resolution of Eczema with Multivalent Peptides

“…Genetic mutations ( Bin et al., 2021 ; Ma et al., 2017 ) and environmental allergens ( Sözener et al, 2020 ; Werfel et al., 2016 ) are risk factors for eczema. The prototypic genetic deficiency is loss-of-function mutations in the gene encoding the protein proFLG ( Hoober and Eggink, 2022 ; Irvine et al., 2011 ; Smith et al., 2006 ). ProFLG is synthesized in the granular layer of the epidermis as a polyprotein that contains 10‒12 repeating domains in humans ( Gan et al., 1990 ) but 20 repeats in the mouse ( Rothnagel and Steinert, 1990 ) and rat ( Haydock and Dale, 1990 ).…”