The skin relies on a sophisticated structure to act as a protective shield against the outside world. This barrier function is heavily influenced by genetics, where a single gene can determine the difference between healthy, resilient skin and a fragile, reactive surface. The FLG gene, which codes for the protein Filaggrin, is a major player in maintaining this outer integrity. Defects in the instructions carried by this gene are strongly associated with chronic skin conditions, most notably atopic dermatitis, also known as eczema.
The Function of Filaggrin in Healthy Skin
Filaggrin is a protein manufactured within the epidermal cells of the outermost skin layer, the stratum corneum, where it performs two distinct roles. The protein is initially synthesized as a large, inactive precursor called profilaggrin, which is stored in specialized structures within the skin cells. As these cells mature and move toward the skin’s surface, the profilaggrin precursor is processed into active Filaggrin units.
These units perform their first mechanical function by binding to and aggregating the keratin intermediate filaments inside the skin cells. This aggregation causes the cells to flatten and collapse, forming a compact, durable structure known as the cornified envelope. The resulting dense, flattened cells are tightly packed together, providing the physical strength and cohesion necessary for the skin’s primary barrier.
The second function occurs when Filaggrin is further broken down by specific enzymes in the uppermost layers of the stratum corneum. This degradation yields a mixture of hydrophilic compounds, including free amino acids, which collectively form the Natural Moisturizing Factor (NMF). NMF is responsible for attracting and retaining water within the skin cells, maintaining the skin’s hydration and flexibility. Furthermore, NMF helps maintain the naturally slightly acidic pH of the skin, which is important for regulating enzyme activity and discouraging pathogen growth.
Genetic Mutations That Impair the Skin Barrier
A genetic defect in the instructions for the FLG gene is the most common single-gene cause of impaired skin barrier function. These defects are known as loss-of-function variants, meaning the resulting protein is either non-functional or produced in insufficient quantities. The consequence of this genetic error is a significant deficiency in functional Filaggrin within the skin’s outermost layer.
This shortage directly compromises the structural integrity of the skin barrier, leading to cells that are less tightly packed and a cornified envelope that is less robust. The subsequent lack of Filaggrin breakdown also results in severely reduced levels of Natural Moisturizing Factor. This combined structural and hydration failure causes the skin to become chronically dry and “leaky.”
A measurable sign of this impairment is an increase in Transepidermal Water Loss (TEWL), where water evaporates through the compromised skin barrier at an accelerated rate. The defective barrier also creates a pathway for foreign substances to penetrate the skin more easily. Allergens, irritants, and environmental pathogens can pass through the weakened outer layer, triggering a localized immune response and inflammation beneath the surface.
These FLG loss-of-function mutations are particularly common, with a high prevalence observed in populations of European and Asian descent. An individual carrying a single copy of a defective FLG gene has a higher risk for skin conditions, while those carrying two copies—one from each parent—often experience more severe and persistent barrier dysfunction.
Eczema and the Atopic March Connection
The barrier dysfunction caused by defective Filaggrin is directly linked to the development of Atopic Dermatitis, a chronic inflammatory skin condition characterized by dry, itchy, and inflamed patches. The increased permeability of the skin allows environmental allergens, such as dust mites or pollen, to enter the body through the skin rather than the respiratory or digestive systems. This exposure through the skin facilitates a process called systemic sensitization.
Once allergens penetrate the compromised barrier, they interact with immune cells beneath the skin’s surface, initiating an inflammatory cascade that results in the characteristic redness, itching, and thickening of eczema. The inflammation itself can further suppress the expression of Filaggrin, creating a feedback loop that exacerbates the skin barrier defect.
This condition often begins in infancy and represents the first step in a sequence of allergic diseases known as the “Atopic March.” The Atopic March describes the natural progression where an individual first develops eczema, which then predisposes them to other allergic conditions later in childhood and adolescence.
The skin-based sensitization to allergens, enabled by the FLG deficiency, is thought to prime the immune system for a broader allergic response. Following the initial onset of eczema, FLG mutation carriers are at an elevated risk of developing food allergies, allergic rhinitis (hay fever), and allergic asthma. The link between FLG mutations and the Atopic March is strongest for food allergies and eczema-associated asthma. This sequence highlights the skin’s role as the initial site of immune system sensitization, demonstrating how a localized genetic defect can lead to systemic, multi-organ allergic diseases over time.
Managing FLG-Related Skin Conditions
Understanding the underlying FLG deficiency provides a clear rationale for targeted management strategies focused on barrier repair. The primary goal of treatment is to compensate for the genetically determined lack of Filaggrin and Natural Moisturizing Factor. This is accomplished through the consistent and generous application of high-lipid moisturizers and emollients.
These products supply the necessary fats and water-binding ingredients to the skin’s surface, effectively replacing the missing NMF and creating an artificial protective layer. Regular barrier repair helps to reduce Transepidermal Water Loss and prevents the entry of irritants and allergens, thereby dampening the inflammatory cycle. Management also involves avoiding known environmental triggers that exploit the existing weakness in the barrier, such as harsh soaps or prolonged exposure to extreme temperatures.
Future treatments are exploring ways to directly address the protein deficiency. Approaches include indirect Filaggrin replacement, such as using topical creams containing components of the Natural Moisturizing Factor, like L-histidine, to restore skin hydration and pH. Researchers are also investigating small molecule therapies, such as Janus kinase (JAK) inhibitors, which show promise in restoring Filaggrin expression suppressed by inflammation.