How Do FLG Gene Mutations Cause Ichthyosis Vulgaris?

Ichthyosis vulgaris is an inherited skin condition primarily caused by pathogenic, loss-of-function variants in the FLG gene ^[1]. This gene provides instructions for making filaggrin, a vital keratin-organizing protein that helps your skin retain water and build a strong barrier ^[1][2].

When the FLG gene is altered, your body may produce less filaggrin, or the protein may not function correctly ^[1][3]. Without sufficient working filaggrin, your skin barrier becomes disorganized and more permeable, allowing water to escape and external irritants to enter ^[3][4]. This dryness reduces the efficiency of the natural enzymes that help your skin shed normally; as a result, older skin cells pile up into the dry, visible scales characteristic of ichthyosis vulgaris ^[4]. Importantly, this condition is not contagious, nor is it caused by poor hygiene.

What This Means For You:

• A filaggrin deficiency weakens the skin barrier and increases water loss ^[5].
• Symptoms often fluctuate with climate, age, and whether there is underlying skin inflammation ^[6][7].
• While daily moisturization cannot change your genes, it is highly effective at managing symptoms ^[8].

To understand exactly how this happens, it helps to look at the three main stages of filaggrin’s lifecycle in the skin.

1. From Profilaggrin to Filaggrin

Deep within the outer layer of your skin (the epidermis), your cells produce a large precursor protein called profilaggrin, which is stored in specialized structures called keratohyalin granules ^[1]. As skin cells mature and move toward the surface, specific enzymes cut this large profilaggrin into smaller, active pieces known as filaggrin monomers ^[1][9].

2. Organizing Keratin Inside the Cell

Once active, filaggrin functions as a crucial organizing protein. Inside the developing skin cells, it binds to keratin—tough structural proteins—and bundles them tightly together ^[1][10]. This binding helps the cells flatten out into tough discs called corneocytes ^[1].

You can think of the outer skin barrier as a brick wall: the flattened corneocytes are the “bricks,” and they are surrounded by a “mortar” of natural lipids (fats). Filaggrin is essential for building strong bricks ^[3]. Without enough filaggrin, the internal structure of these cells is disorganized, leading to a weaker overall barrier ^[3].

3. Natural Moisturizing Factors (The Skin’s Sponge)

When those flattened skin cells reach the very top layer of your skin (the stratum corneum), filaggrin is broken down into a mixture of amino acids and derivatives known as natural moisturizing factor (NMF) ^[1][4]. NMF includes substances like urea, which are hygroscopic—meaning they act like microscopic sponges that pull in and hold onto water ^[4].

If you have an FLG variant, your skin may produce less NMF. Without these microscopic sponges, your skin loses water rapidly to the air, a process called transepidermal water loss (TEWL) ^[4][5]. The enzymes responsible for normal skin shedding require a certain level of hydration to work efficiently; when the skin becomes too dry, shedding slows down, and dead cells remain stuck to the surface as rough scales ^[4].

While topical moisturizers containing urea can improve hydration and soften these scales ^[8], they do not replace the missing filaggrin protein or cure the genetic cause. (Note: Urea can sometimes sting on cracked or severely inflamed skin; ask your clinician or pharmacist about the appropriate concentration for your body).

One Copy vs. Two Copies of the Gene

You inherit two copies of the FLG gene—one from each parent.

• One pathogenic variant (Heterozygous): Carrying one altered copy increases the risk of barrier dysfunction and usually leads to mild to moderate dry skin and scaling ^[11].
• Two pathogenic variants (Biallelic): Carrying two altered copies generally results in little to no functional filaggrin, which often leads to more pronounced and widespread scaling ^[11][3].

However, gene copies do not perfectly predict your exact symptoms ^[12]. Some people with two altered copies have moderate symptoms, while others with just one copy have highly visible scaling ^[11]. Clinical appearance alone cannot reliably determine your exact genotype ^[13]. Furthermore, not everyone with clinically typical ichthyosis vulgaris has an identifiable FLG variant, as other biological and environmental factors play important roles ^[3][14].

The Role of Environment and Eczema

Because the severity of ichthyosis vulgaris isn’t strictly determined by your genes, other factors strongly influence how your skin behaves:

• The Environment: Cold, dry winter air pulls water from your vulnerable skin, commonly worsening symptoms during winter months ^[6]. Prolonged hot baths and harsh cleansers can also strip the barrier ^[15].
• Eczema (Atopic Dermatitis): FLG loss-of-function variants are a major inherited risk factor for eczema, though developing eczema is not inevitable ^[2][16]. A weakened barrier makes it easier for allergens and irritants to enter the skin ^[17][18]. If eczema does develop, the resulting inflammation can further suppress the filaggrin your body is able to produce, acting as an additional mechanism that worsens barrier breakdown ^[7][19].

Warning signs of eczema or infection to watch for include new redness, intense itching, painful cracks (fissures), oozing, or crusting. Contact your clinician if you experience rapidly worsening skin symptoms.