FLG

In one line: FLG builds the protein that packs your skin into a waterproof wall and becomes the skin's own moisturizer — break it, and the barrier leaks, making a broken copy the single strongest genetic risk factor known for eczema and the opening act of allergic disease.

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The gene

FLG sits on chromosome 1q21.3, inside a tight cluster of skin-barrier genes called the epidermal differentiation complex. It encodes filaggrin — short for "filament-aggregating protein," the name Peter Steinert and Beverly Dale gave it in 1981 for what it does. The protein is made as a giant, repetitive precursor, profilaggrin, stored in the granules of the skin's upper layer; as those cells terminally differentiate, profilaggrin is cleaved into many copies of the working filaggrin monomer. About 1 in 10 people of European ancestry carry at least one broken (loss-of-function) copy.

The hunt — and the scientist

For decades the gene hid in plain sight. The protein was well characterised, but its gene resisted everyone, because the core of FLG (exon 3) is a giant run of near-identical tandem repeats that ordinary short-read PCR sequencing simply cannot resolve. In 2006, a team led by W. H. Irwin McLean at the University of Dundee finally cracked it — using long-range PCR to amplify the whole repeat region and reassembling it from overlapping fragments like a jigsaw. It was a genuine team achievement: Frances Smith was first author on the ichthyosis-vulgaris paper, Colin Palmer on the atopic-dermatitis paper, and Alan Irvine (Dublin) was a co-driver throughout. Two "off-switch" mutations kept surfacing in European families — R501X and 2282del4 (different populations carry different FLG-null mutations). Starting from ichthyosis vulgaris — the most common inherited dry, scaly skin, a semidominant trait — they showed those same variants were also a major risk factor for eczema.

The mechanism

The stratum corneum is a "bricks and mortar" wall: flattened dead cells (corneocytes) are the bricks, lipids are the mortar. Filaggrin works inside the bricks, doing two jobs. First it aggregates keratin filaments, collapsing each cell into a tough, flat plate. Then filaggrin is itself broken down into a pool of amino acids and acids — "natural moisturizing factor" (NMF), including PCA and urocanic acid — the skin's own built-in humectant that holds water and helps keep the surface slightly acidic. Lose filaggrin and you lose both: the bricks don't pack tight, the moisturizer isn't made, water escapes (raised transepidermal water loss), and the barrier leaks. Allergens and microbes then penetrate the broken barrier, and the immune system — meeting them through the skin — is sensitised. This is the "outside-in" model: barrier first, allergy second. (It is the leading model from the genetic evidence, though the biology is bidirectional — immune signals like IL-4/IL-13 also suppress filaggrin.)

The stakes, and how to use it

A leaky barrier in infancy is now seen as the opening act of the "atopic march" — eczema, then food allergy, then asthma and allergic rhinitis. Notably, FLG raises asthma risk mainly in the context of eczema (there is no filaggrin in the airway) — the sensitisation route is the skin, not the lung; FLG loss is even linked to peanut allergy.

The discovery's biggest practical legacy is conceptual: it reframed eczema from a purely immune mystery into a barrier disease you can help repair, putting gentle, barrier-friendly moisturisers front-line for treatment. One honest caveat matters, though: moisturising every newborn does not prevent eczema. Two large randomised trials — BEEP and PreventADALL (both Lancet 2020) — found daily emollient did not prevent atopic dermatitis, and BEEP saw a signal of more skin infections. Emollients manage the barrier; they don't rewrite the gene. And there is no filaggrin "fix" yet — today's best drugs (e.g. dupilumab) calm the immune half of the loop, restoring filaggrin only indirectly. FLG genotyping remains a research tool, not routine clinical care.

Sources

Full claim-by-claim evidence is in references.md. Primary anchors:

• Smith FJD, Irvine AD, … McLean WHI. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006. [PMID 16444271]
• Palmer CNA, Irvine AD, … McLean WHI. Common loss-of-function variants of filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006. [PMID 16550169]
• Irvine AD, McLean WHI, Leung DYM. Filaggrin mutations associated with skin and allergic diseases. NEJM 2011. [PMID 21991953]
• Brown SJ, McLean WHI. One remarkable molecule: Filaggrin. J Invest Dermatol 2012. [PMC3378480]
• van den Oord RA, Sheikh A. Filaggrin gene defects and risk of allergic sensitisation and disorders: systematic review & meta-analysis. BMJ 2009. [PMC2714678]
• Chalmers JR et al. Daily emollient during infancy for prevention of eczema (BEEP). Lancet 2020. [PMID 32113509] · Skjerven HA et al. PreventADALL. Lancet 2020. [PMID 32113507]

Accuracy note: the episode is careful to say FLG nulls cause ichthyosis vulgaris (semidominant Mendelian) but are a risk factor for atopic dermatitis (complex disease); to credit the team, not a lone scientist; to mark R501X/2282del4 as European-specific; to keep filaggrin intracellular (NMF is its breakdown product, not the lipid mortar); to route asthma risk through eczema; to separate emollients-as-treatment from the negative prevention trials; and to soften the contested skin-pH claim.