Filaggrin

Filaggrin is a filament-associated is_associated_with::protein that binds to is_associated_with::keratin fibers in epithelial cells.

Profilaggrin
Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the is_associated_with::stratum granulosum. Profilaggrin undergoes proteolytic processing to yield individual filaggrin monomers at the transition between the is_associated_with::stratum granulosum and the is_associated_with::stratum corneum, which may be facilitated by is_associated_with::calcium-dependent is_associated_with::enzymes.

Function
Filaggrin is essential for the regulation of epidermal homeostasis. Within the is_associated_with::stratum corneum, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin is_associated_with::intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free is_associated_with::amino acids that assist in water retention.

Clinical significance
Individuals with truncation is_associated_with::mutations in the is_associated_with::gene coding for filaggrin are strongly predisposed to a severe form of dry skin, is_associated_with::ichthyosis vulgaris, and/or is_associated_with::eczema.

It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene. R501X and 2284del4 are not generally found in non-Caucasian individuals, though novel mutations (3321delA and S2554X) that yield similar effects have been found in Japanese populations. Truncation mutations R501X and 2284del4 are the most common mutations in the Caucasian population, with 7 to 10% of the Caucasian population carrying at least one copy of these mutations.

is_associated_with::Autoantibodies in is_associated_with::rheumatoid arthritis recognizing an is_associated_with::epitope of citrullinated peptides are cross-reactive with filaggrin.

The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations. Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.

In early infancy, the penetrance of filaggrin mutations may be increased by household exposure to cats.