Filaggrin is a structural protein found in the outermost layer of human skin, the epidermis. It is synthesized first as a much larger, inactive precursor known as profilaggrin, which is stored in specialized granules within skin cells. Filaggrin’s primary purpose is to organize the internal structure of the skin’s surface cells, providing mechanical strength to the protective layer. This protein is foundational to the skin’s ability to maintain hydration and act as a functional barrier against the external environment, essential for maintaining overall skin health and integrity.
Filaggrin’s Role in Skin Structure and Barrier Function
The mature filaggrin protein plays a dual role in maintaining the integrity of the stratum corneum. Initially, its function is mechanical, where it bundles and aggregates the keratin intermediate filaments within the flattened skin cells, known as corneocytes. This process is crucial for collapsing and flattening the cells, which forms the dense, compact structure often compared to the “bricks” in the skin’s protective barrier. This compaction provides the skin with robust physical strength and resistance to external stresses.
In the final stages of the skin cell lifecycle, filaggrin undergoes an enzymatic breakdown process. This degradation yields a complex mixture of smaller, water-soluble molecules, including free amino acids and derivatives like pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). These hygroscopic molecules collectively form the Natural Moisturizing Factor (NMF), which draws in and holds water within the corneocytes.
NMF accounts for a significant portion of the stratum corneum’s water-holding capacity, ensuring the skin remains hydrated and supple, even in dry conditions. Filaggrin breakdown products also help maintain the skin’s slightly acidic surface pH, which is necessary for the proper function of enzymes that regulate skin barrier homeostasis.
The Genetic Blueprint: Understanding the FLG Gene
The instructions for creating the filaggrin protein are encoded by the FLG gene, located on chromosome 1 within the epidermal differentiation complex. This gene is unusual because the part encoding the repetitive filaggrin units is contained within a single, large exon. The FLG gene directs the production of the precursor protein, profilaggrin, which is then processed into multiple individual filaggrin monomers.
Many skin conditions are linked to specific loss-of-function or “null” mutations in the FLG gene. These mutations often introduce a premature stop signal, resulting in an abnormally short or non-functional profilaggrin molecule. Consequently, skin cells cannot produce the correct amount of functional filaggrin protein, leading to a deficiency.
The inheritance pattern is semi-dominant: inheriting a mutation in just one copy of the FLG gene (heterozygous) increases the risk of skin disease, though symptoms may be milder. Inheriting a mutation in both copies (homozygous or compound heterozygous) typically results in a more severe skin barrier defect and a greater likelihood of developing associated conditions. Up to 10% of individuals in some populations of European descent carry a loss-of-function mutation.
Filaggrin Deficiency and Associated Skin Conditions
A deficiency of functional filaggrin protein has profound consequences for the skin’s barrier function. Without sufficient filaggrin, the structural integrity of the stratum corneum is compromised, leading to a “leaky” barrier. This defective barrier results in increased Transepidermal Water Loss (TEWL), where water evaporates too easily from the skin, causing severe dryness and scaling.
The lack of filaggrin also severely reduces the amount of Natural Moisturizing Factor (NMF) produced in the skin, exacerbating the dryness. This structural and hydrational failure is strongly linked to Atopic Dermatitis, commonly known as Eczema. Individuals with FLG null mutations have a significantly higher risk of developing this chronic inflammatory skin condition.
The compromised skin barrier also plays a central role in the “Atopic March,” the natural progression of allergic diseases. This progression often begins with eczema in infancy and moves to food allergies, allergic rhinitis, and asthma later in childhood. The defective barrier allows environmental allergens, such as dust mites or food proteins, to penetrate the skin easily, triggering a systemic immune response that drives the progression of the march.
Supporting the Skin Barrier: Treatment Strategies
Management of conditions related to filaggrin deficiency centers on restoring and supporting the compromised skin barrier function. Topical treatments are designed to replace the lost components and physically repair the surface layer.
Topical Treatments
Frequent and liberal application of emollients, which are moisturizing creams and ointments, is a foundational part of the daily regimen. These products work by providing lipids and water to the stratum corneum, helping to reduce water loss and improve skin hydration.
More advanced barrier repair formulations often contain ingredients that mimic the skin’s natural components, effectively acting as replacement therapy. This includes humectants, such as urea and glycerin, which function similarly to the missing Natural Moisturizing Factor components by drawing moisture into the skin. Some moisturizers also incorporate ingredients like ceramides, which are the main lipid components of the skin barrier’s “mortar,” helping to reorganize the lipid layers and improve cohesion. Research is also exploring novel topical agents, such as L-histidine or cis-urocanic acid, that aim to indirectly or directly compensate for the loss of filaggrin-derived molecules.
Lifestyle Adjustments
Lifestyle adjustments are also important for minimizing further damage to the already fragile barrier. This includes avoiding harsh soaps and detergents, which can strip the skin of its remaining natural oils and further deplete NMF components. Using gentle, non-foaming cleansers and avoiding excessively hot or prolonged water exposure helps maintain the skin’s surface pH and prevents the washing away of protective lipids and moisturizing factors.