Filaggrin and the great epidermal barrier grief

Abstract

One of the principal functions of human skin is to form an effective mechanical barrier against the external environment. This involves the maturation and death of epidermal keratinocytes as well as the assembly of a complex network of differentially and spatially expressed proteins, glycoproteins and lipids into the keratinocyte cell membrane and surrounding extracellular space. In 2006, the key role of the granular cell layer protein filaggrin (filament-aggregating protein) in maintaining the skin barrier was determined with the identification of loss-of-function mutations in the profilaggrin gene (FLG). These mutations have been shown to be the cause of ichthyosis vulgaris and a major risk factor for the development of atopic dermatitis, asthma associated with atopic dermatitis as well as systemic allergies. Mutations in the FLG gene are extremely common, occurring in approximately 9% of individuals from European populations. The remarkable discovery of these widespread mutations is expected to have a major impact on the classification and management of many patients with ichthyosis and atopic disease. It is also hoped that the genetic discovery of FLG mutations will lead to the future development of more specific, non-immunosuppressive treatments capable of restoring effective skin barrier function and alleviating or preventing disease in susceptible individuals.

Deimination is regulated at multiple levels including auto-deimination of peptidylarginine deiminases

“…Importantly, a reduced amount of filaggrin, which is associated with reduced levels of hygroscopic amino acids and altered barrier functions, underlies ichthyosis vulgaris (OMIM 146700) and is a major risk factor for atopic dermatitis (OMIM 603165), two very common skin diseases often associated with rhinitis and asthma. The known reasons for filaggrin decrease are profilaggrin-gene null mutations [11][12][13] and cytokine-induced down-regulation [14,15]. Defective PAD activities can also be suspected since in vitro deimination of filaggrin increases its proteolysis by calpain I and bleomycin-hydrolase, two proteases involved in its processing in the lower stratum corneum [16].…”

Application of genetic/genomic approaches to allergic disorders

“…Using a candidate gene approach, common mutations in filaggrin gene (FLG, 1q21) have been implicated in the causation of ichthyosis vulgaris77–79. Filaggrin80 (filament aggregation protein) is a major epidermal protein involved in maintaining the skin barrier81 and previous studies had demonstrated that filaggrin was absent or reduced in the skin cells of individuals with ichthyosis vulgaris82.…”

The frequency of polymorphic variants of filaggrin gene and clinical atopic dermatitis

“…Its precursor is rich in histidine, highly phosphorylated polypeptide-profilaggrin, which is the main component of the granularity of keratohyalin granular layer of epidermis [4]. Filaggrin metabolism is associated with an acidic pH of the stratum corneum, which is the optimal environment for the enzyme synthesizing lipids, and also contributes to the so-called natural moisturizing factor (NMF).…”