filaggrinegen

The filaggrin gene, abbreviated FLG, encodes profilaggrin, a large precursor protein expressed in keratinocytes of the epidermis. Profilaggrin is cleaved to filaggrin monomers that bind and compact keratin intermediate filaments, promoting the formation of a properly structured stratum corneum. During later processing, filaggrin breakdown products become natural moisturizing factors (NMF), including compounds such as urocanic acid and pyrrolidone carboxylic acid, which help maintain skin hydration, pH, and barrier integrity.

FLG is located on chromosome 1q21 within the epidermal differentiation complex and comprises repetitive regions that contribute to its size and regulation. Loss-of-function variants in FLG reduce or abolish filaggrin production, compromising the skin barrier.

Genetic variation and inheritance: The FLG gene harbors several common loss-of-function variants. In many European populations, examples include R501X and 2282del4, among others; different variants are observed in Asian and other populations. The effects show a dosage relationship: individuals with one null allele (heterozygotes) have an increased risk of barrier-related conditions, while those with two null alleles (homozygotes or compound heterozygotes) tend to have higher risk and often more severe manifestations.

Clinical significance: FLG deficiency is strongly associated with ichthyosis vulgaris and atopic dermatitis (eczema). Barrier impairment facilitates transepidermal water loss, allergen penetration, and susceptibility to skin infections, and it may contribute to other atopic diseases in some individuals. Diagnosis can involve genetic testing in selected cases, while management focuses on restoring and maintaining barrier function with regular moisturizers, emollients, and strategies to reduce irritant exposure.