FLG

Filaggrin, encoded by FLG, is one of the clearest examples in human genetics of a single structural protein whose loss produces a coherent chain of visible consequences: dry, scaly skin in childhood, a markedly increased risk of eczema, and a higher chance of progressing to asthma and allergic rhinitis later in life. The gene sits within the epidermal differentiation complex on chromosome 1, a cluster of genes that coordinate the final stages of keratinocyte maturation into the tough, flattened corneocytes of the stratum corneum.

FLG is synthesized as an enormous precursor called profilaggrin, stored in keratohyalin granules near the top of the epidermis. As keratinocytes complete their terminal differentiation, proteases including caspase-14 and SASPase cleave profilaggrin into individual filaggrin monomers. These monomers bind and aggregate keratin intermediate filaments, collapsing the cell into the flattened, mechanically tough corneocyte shape that forms the outermost physical barrier of the skin.

Filaggrin's job does not end with structural support. Almost as soon as it has done its work aggregating keratin, filaggrin is itself degraded further, down to free amino acids such as glutamine, histidine, and serine. These amino acids and their downstream metabolites, particularly pyrrolidone carboxylic acid and urocanic acid, make up the bulk of what dermatologists call the natural moisturizing factor (NMF). NMF is a set of small, highly hygroscopic molecules that hold water inside corneocytes even in a dry external environment, while urocanic acid also absorbs ultraviolet radiation and helps maintain the mildly acidic pH of the skin surface.

Because FLG contains a large, imperfect array of nearly identical repeat sequences, it is unusually prone to loss-of-function mutations, and two such variants, R501X and 2282del4, are carried by up to one in ten people of Northern European descent. Carriers produce truncated, non-functional profilaggrin, leading to a thinner, leakier stratum corneum with reduced NMF. This single genetic change is the strongest known risk factor for atopic dermatitis and is sufficient on its own to cause ichthyosis vulgaris, illustrating how one structural protein bridges cosmetic dryness, chronic inflammatory skin disease, and the broader allergic disease trajectory known as the atopic march.

Overview

Filaggrin, encoded by FLG, is one of the clearest examples in human genetics of a single structural protein whose loss produces a coherent chain of visible consequences: dry, scaly skin in childhood, a markedly increased risk of eczema, and a higher chance of progressing to asthma and allergic rhinitis later in life. The gene sits within the epidermal differentiation complex on chromosome 1, a cluster of genes that coordinate the final stages of keratinocyte maturation into the tough, flattened corneocytes of the stratum corneum.

FLG is synthesized as an enormous precursor called profilaggrin, stored in keratohyalin granules near the top of the epidermis. As keratinocytes complete their terminal differentiation, proteases including caspase-14 and SASPase cleave profilaggrin into individual filaggrin monomers. These monomers bind and aggregate keratin intermediate filaments, collapsing the cell into the flattened, mechanically tough corneocyte shape that forms the outermost physical barrier of the skin.

Filaggrin’s job does not end with structural support. Almost as soon as it has done its work aggregating keratin, filaggrin is itself degraded further, down to free amino acids such as glutamine, histidine, and serine. These amino acids and their downstream metabolites, particularly pyrrolidone carboxylic acid and urocanic acid, make up the bulk of what dermatologists call the natural moisturizing factor (NMF). NMF is a set of small, highly hygroscopic molecules that hold water inside corneocytes even in a dry external environment, while urocanic acid also absorbs ultraviolet radiation and helps maintain the mildly acidic pH of the skin surface.

Because FLG contains a large, imperfect array of nearly identical repeat sequences, it is unusually prone to loss-of-function mutations, and two such variants, R501X and 2282del4, are carried by up to one in ten people of Northern European descent. Carriers produce truncated, non-functional profilaggrin, leading to a thinner, leakier stratum corneum with reduced NMF. This single genetic change is the strongest known risk factor for atopic dermatitis and is sufficient on its own to cause ichthyosis vulgaris, illustrating how one structural protein bridges cosmetic dryness, chronic inflammatory skin disease, and the broader allergic disease trajectory known as the atopic march.

Deep Dive

From Precursor to Monomer: A Tightly Timed Proteolytic Cascade

Profilaggrin is not biologically active in its stored form. It must be released from keratohyalin granules and cleaved at multiple sites to yield free filaggrin monomers, and this process is deliberately delayed until keratinocytes reach the uppermost granular layer.

• Dephosphorylation precedes cleavage. Profilaggrin is heavily phosphorylated in the granular layer, which keeps it inactive and aggregated within keratohyalin granules; dephosphorylation is a prerequisite for proteolytic processing to begin.
• A relay of proteases completes the job. Calpain-1, matriptase (via the protease PRSS8 pathway), SASPase (ASPRV1), and caspase-14 act in a coordinated sequence to cut profilaggrin into individual monomers and then trim their linker sequences.
• Timing matters. Premature processing would waste filaggrin’s structural role in the lower granular layer; the delay ensures filaggrin monomers appear exactly when keratin bundling is needed most, just before corneocytes flatten.

Two Roles for One Protein: Structural Scaffold, Then Humectant Precursor

Filaggrin performs two sequential and seemingly contradictory jobs, first holding the cytoskeleton together and then dissolving into small molecules that hold water.

• Structural phase. Filaggrin monomers cross-link keratin intermediate filaments into tight macrofibrils, physically collapsing the keratinocyte into a flattened, mechanically resilient corneocyte.
• Humectant phase. Once this structural task is complete, filaggrin is further degraded by bleomycin hydrolase, caspase-14, and arginase into free amino acids, several of which are converted into pyrrolidone carboxylic acid and urocanic acid.
• A single protein, two jobs, two locations. This sequence means that a defect anywhere along the profilaggrin-to-NMF pathway, not just in FLG itself, can produce a filaggrin-deficient phenotype, which is part of why some individuals without FLG mutations still show reduced NMF.

Pathogenic Variants: Why Null Mutations Dominate the Genetic Landscape

Unlike many disease genes where missense mutations subtly alter protein function, the FLG mutation spectrum is dominated by mutations that simply eliminate protein production altogether.

• Premature stop codons and frameshifts. R501X (a nonsense mutation) and 2282del4 (a frameshift deletion) both truncate profilaggrin before most of its repeat units can be translated, effectively halting filaggrin monomer production from that allele.
• Population-specific mutation spectra. While R501X and 2282del4 dominate in Northern European populations, East Asian populations carry a largely distinct set of FLG null alleles, meaning genetic testing panels must be population-aware.
• Semi-dominant inheritance with dose effects. A single null allele increases eczema and dry skin risk; carrying two null alleles (homozygous or compound heterozygous) produces more severe ichthyosis vulgaris and higher atopic dermatitis risk, consistent with a straightforward gene-dosage effect on total filaggrin output.

Feedback Loops: Genetics Meets Acquired Inflammation

FLG genotype is only part of the story. Inflammatory signaling can suppress filaggrin expression even in genetically normal skin, creating a self-reinforcing cycle in active atopic dermatitis.

• Th2 cytokines silence FLG transcription. IL-4 and IL-13, hallmark cytokines of type 2 inflammation, signal through STAT6 to reduce filaggrin gene expression in keratinocytes, independent of the underlying FLG genotype.
• A barrier-inflammation feedback loop. A weaker barrier allows more allergen and irritant penetration, which drives more Th2 inflammation, which further suppresses filaggrin, worsening the barrier again. This loop helps explain why atopic dermatitis often becomes self-perpetuating once established.
• Therapeutic implications. Biologics that block IL-4 and IL-13 signaling, such as dupilumab, can partially restore filaggrin expression by interrupting this cytokine-driven suppression, independent of any effect on the patient’s underlying genotype.

Biomarker and Barrier-Testing Interpretation

Clinical and research assessment of filaggrin status generally relies on indirect barrier measures rather than direct filaggrin protein quantification.

• Transepidermal water loss (TEWL) reflects barrier integrity broadly, not filaggrin specifically; elevated TEWL can result from filaggrin deficiency, active inflammation, or both simultaneously.
• Genotyping only captures known alleles. Targeted panels for R501X and 2282del4 will miss rarer or population-specific null mutations, so a negative genotype result does not exclude filaggrin insufficiency from other pathway defects.
• NMF and corneometry are functional readouts, useful for tracking response to barrier-supportive treatment even when the underlying genetic cause is not fully characterized.