The main function of the skin is to act as a barrier that separates the internal environment from the external one, thus protecting against aggression by exogenous agents and minimizing the loss of water and other essential body components to the external space.1 Filaggrin is particularly important in the formation of the skin barrier, both for its fundamental role in terminal epidermal differentiation and for its implication in some of the most common dermatological diseases, such as atopic dermatitis (AD) and ichthyosis vulgaris.2 Filaggrin is an important structural protein that was first identified in 1977.3 Later, when it was found to produce aggregation and compaction of keratin intermediate filaments, it was named filaggrin, the acronym of filament-aggregating protein.4 This protein is synthesized as a giant precursor protein called profilaggrin, which is the main component of the keratohyalin granules in the stratum granulosum of the epidermis.

The main element of the skin barrier is the stratum corneum. This stratum is the end-product of the differentiation of keratinocytes, which, from the basal layer to the granulosum layer, are viable nucleated cells. These cells express various structural proteins as they mature.5 In the final steps of differentiation, the keratinocytes undergo marked changes in their structure, leading to their transformation into flat, anucleate squamous cells, the corneocytes. These corneocytes, which remain tightly bound together by corneodesmosomes, are covered by a cellular coating called the cornified envelope (CE), which has protein and lipid components that endow the cells with mechanical and chemical resistance.5 Between the cells there is a hydrophobic, lipid-rich extracellular matrix arranged in a laminar bilayer.6 This organization of the stratum corneum has been called “bricks and mortar”, in which the keratinocytes are the bricks and the extracellular lipid matrix is the mortar.7

A calcium gradient exists in the epidermis, with low concentrations in the basal layer, even lower concentrations in the stratum spinosum, high levels in the stratum granulosum, and very low levels in the stratum corneum.8 This gradient is important in terminal keratinocyte differentiation.2,9 The higher concentration of calcium in the stratum granulosum causes the keratohyalin granules to release their contents, leaving the profilaggrin exposed to undergo processing and fragmentation into active filaggrin monomers.10 This free filaggrin binds to the intermediate keratin filaments, causing their aggregation and compaction, provoking the collapse and flattening of the cell. Simultaneously, the cell expresses a series of structural proteins that make up the protein portion of the CE.11,12 The bundles of keratin intermediate filaments aggregated by filaggrin bind to these structural proteins through the action of transglutaminases.6 In addition, the increase in the calcium concentration also provokes release of the contents of the lamellar bodies, which are granules rich in lipids and enzymes synthesized in the Golgi apparatus. The action of these enzymes on the lipids gives rise to the lipid portion of the CE and the extracellular matrix of the stratum corneum.6,11,13

Filaggrin continues to undergo processing by various proteases. This proteolysis leads to the release of hygroscopic amino acids and their derivatives, which form natural moisturizing factor (NMF), responsible for water retention in the stratum corneum.14 The breakdown of some of these amino acids gives rise to 2 organic acids: trans-urocanic acid (UCA), a histidine derivative; and pyrrolidone-5-carboxylic acid (PCA), a glutamine derivative. These acids are 2 of the main factors responsible for maintaining the acid pH of the stratum corneum,15 which is essential for its role in the metabolism and organization of the lipids of the extracellular matrix,16 for its antimicrobial action, and for its regulatory role on enzyme activity and physiologic desquamation.17 In addition, UCA has a photoprotective effect against UV radiation18 and has been shown to be a key mediator in UV-B–induced immunosuppression.19,20

Filaggrin deficit has a major impact on the epidermal barrier (Table 1), affecting the organization of the keratin filaments of the cytoskeleton and the structure of the CE. There is also a fall in the number of keratohyalin granules, a marked fall in NMF concentration (and thus in hydration of the stratum corneum), and alkalinization of the skin pH.5 In addition to these changes, recent ultrastructural studies have shown that a deficit of filaggrin is also associated with a generalized fall in the density of corneodesmosomes and of tight intercellular junctions, as well as with abnormalities in the architecture of the extracellular lipid matrix; these changes may produce a notable alteration of barrier function, provoked by abnormalities in the organization of the cytoskeleton (which affect lamellar body maturation and exocytosis, leading to a nonuniform distribution of secreted lipids and enzymes) and by the increase in the pH (which modulates the activity of those enzymes).16 Furthermore, the increase in the activity of certain proteases caused by the persistent elevation of the pH favors the release of proinflammatory mediators by keratinocytes; these mediators induce an inflammatory response mediated by type 2 helper T (Th2) cells even in the absence of allergens.21 For example, alkalinization of the skin pH increases the activity of the proteases responsible for the production of interleukin (IL) 1α and IL-1β from their inactive proproteins generated by keratinocytes.22

Profilaggrin is coded by the FLG gene, located in the epidermal differentiation complex on chromosome 1 (locus 1q21), a cluster of genes that code for proteins involved in epidermal differentiation.23 The FLG gene is made up of 3 exons and 2 introns (Fig. 1). Transcription starts at exon 2, but it is exon 3 that codes for the greatest part of the protein, constituting one of the largest exons in the genome.24 The resulting protein (profilaggrin) is rich in histidine and contains between 10 and 12 repetitions of filaggrin flanked by N- and C-terminus domains (Fig. 1).

Figure 1.

Structure of the FLG gene and of the profilaggrin protein.

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These domains are also functional. The N-terminus domain is, in turn, formed by 2 subdomains: A andB. Subdomain A contains 2 calcium binding sites.25 It is the binding of calcium to this subdomain that produces a series of conformational changes in the profilaggrin molecule that will initiate its processing.2 The B subdomain contains a nuclear localization signal that facilitates translocation of the N-terminus domain to the cell nucleus when it is cleaved from the rest of the protein.26 It has been suggested that this N-terminus domain, once within the nucleus, plays an important role in the loss of the keratinocyte nucleus during transformation of the cell into an anucleate corneocyte27 and it has also been attributed a role in assembly of the CE.28 The C-terminus domain is essential for correct processing of the profilaggrin, although its exact function is unknown.2

The first mutations identified in the FLG gene were R501X and 2282del4 in patients with ichthyosis vulgaris.29 Many more mutations have been described since that time, but all are loss-of-function mutations (amino acid substitutions or frameshift mutations).21 Furthermore, the mutations have been shown to display ethnic/geographic specificity, with different mutations being detected in the European and Asian populations.30 There is also variation in the frequency of the mutations: 2 mutations (R501X and 2282del4) account for 80% of all FLG mutations in Ireland, whereas in Singapore no single mutation predominates in any such way over the others.21 The overall prevalence of mutations in the general population in Europe is 7.7%, but in Asia is 3%.31 Focusing on European studies, there is a noticeable difference in prevalence between the north and south of the continent. The majority of publications refer to northern populations, with a prevalence of approximately 10% (range, 7%-14%).31 There are only 2 studies in Mediterranean populations, one in a French population32 and the other in an Italian population33; both studies revealed a much lower prevalence (4%).

This apparently latitude-dependent trans-European gradient, led the Italian authors to put forward that perhaps FLG mutations offer some form of survival benefit in the north.33 It has been suggested that this could be related to a lower level of UCA found in these patients; this would produce greater sensitivity to UV radiation.18,32,34 Recent population-based studies have revealed that individuals with FLG mutations have serum vitamin D levels that are 10% higher than controls.35 Overall, these data show that in latitudes with a lower intensity of UV radiation, individuals with FLG mutations may have greater protection against the onset of diseases such as rickets.31

Table 2 lists the disorders that have been associated with a filaggrin deficit caused by mutations in the FLG gene; the main diseases are ichthyosis vulgaris and atopic disorders.

Ichthyosis vulgaris is the most common disorder of keratinization, with an estimated prevalence between 1 in 80 and 1 in 250 in school-age English children,15 and is the disease of mendelian inheritance caused by mutations in the FLG gene.31 The absence (or marked reduction) of keratohyalin granules in biopsies from patients with ichthyosis vulgaris was first observed in the 1980s, together with a decrease in filaggrin expression detected using immunostaining techniques.36 However, it was not until 2006 that loss-of-function mutations in the FLG gene were identified as the cause of the condition29; this lag was the result of the long length of the gene and its highly repetitive sequence, which made it difficult to sequence using conventional polymerase chain reaction techniques.15 The discovery of these mutations made it possible to clarify the pattern of disease inheritance; this is autosomal semidominant, which explains the phenotypic variability of ichthyosis vulgaris. Heterozygotic patients present haploinsufficiency, which is a 50% reduction in filaggrin expression. In this situation, patients develop less serious disease (or may even be asymptomatic) and the manifestations respond better to external influences, such as the application of emollient creams or environmental moisture. Homozygotic individuals, on the other hand, develop all the manifestations of the disease.21,29

Clinically, ichthyosis vulgaris is characterized by the appearance of xerosis, keratosis pilaris, palmar hyperlinearity, and atopy in the postnatal period (typically in the first year of life).21 Xerosis is seen as a fine, sometimes polygonal desquamation that mainly affects the extensor surface of the limbs (Fig. 2), scalp, central facial region, and trunk, while the folds are usually spared. The level of moisture modifies filaggrin processing,14,37 which explains the tendency to sparing of the skin folds and why, in the majority of patients, the disease worsens in winter, when environmental humidity is lower.31

Figure 2.

Fine, pale desquamation in a patient with ichthyosis vulgaris.

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Painful fissures on the hands, heels, fingers, and toes are common (present in up to 76% of patients with ichthyosis vulgaris). This is closely related to the level of environmental moisture.31 Furthermore, mutations in the FLG gene have been associated with the onset of fissured dermatitis on the dorsum of the hands and fingers in patients with AD and even in the general population.31,38

Palmar hyperlinearity (Fig. 3) and keratosis pilaris are typical findings not only in patients with clinical manifestations of ichthyosis vulgaris but also in all individuals with FLG mutations. One study found that palmar hyperlinearity had a positive predictive value of 71% and a negative predictive value of 90% for mutations in the FLG gene. That is, 71% of children with palmar hyperlinearity have a mutation, whereas mutations are highly unlikely in patients without palmar hyperlinearity. In the case of keratosis pilaris, the positive predictive value was 53% and the negative predictive value was 90%.39

Figure 3.

Palmar hyperlinearity in a 7-year-old child with ichthyosis vulgaris.

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Finally, 35% to 70% of patients with ichthyosis vulgaris develop atopic disease, particularly dermatitis but also allergic rhinitis and asthma.40 This finding has led to extensive research into the relationship between mutations in the FLG gene and atopic diseases, detecting interesting data on the pathogenesis of these complex disorders.

Atopy is defined as a personal or familial tendency to sensitization and immunoglobulin (Ig) E antibody production in response to exposure to common environmental allergens to which everyone is exposed but to which the majority develop no response.41 This tendency predisposes to the development of the so-called atopic diseases, which affect 20% of the population in developed countries.42 The concept of atopic march was introduced to describe the tendency of AD to precede the sequential onset of asthma and allergic rhinitis,43 which suggests that AD has an initiator role in the process. It has recently been suggested that food allergies may also form part of this atopic march.44

Forty percent of children with AD will finally develop asthma or allergic rhinitis.10 In the case of asthma, the risk correlates with the severity of the skin disease, with 70% of patients with severe AD developing asthma, while this only occurs in 20% to 30% of those with mild AD and 8% of the general population.42 Population-based studies have demonstrated that carriers of FLG mutations have a higher risk of developing asthma, with an overall OR of 1.8.55,70 But that risk is limited to those with AD, in whom the OR rises to 3.3 (95% confidence interval, 3.16-3.49).55,70 Carriers of a mutation also have a higher risk of allergic rhinitis (OR, 2.64), although in this case it is independent of whether or not the patient has eczema.55 Finally, concerning the onset of food allergy, it has been shown that carriers of FLG mutations have a significantly higher risk of developing peanut allergy; this risk is greater if the patient has AD, but is also present independently of AD (overall OR, 5.3, with a residual OR of 3.8 after adjustment for AD).56

Since the discovery of mutations in the FLG gene, numerous studies have been performed to look for a possible relationship with various skin and extracutaneous diseases, whether due to an association with AD, to a similar underlying pathogenesis, or to a shared susceptibility locus.15 A summary of the results of these studies is presented in Tables 2 and 3. Given the high frequency of carriers in the general population, it is likely that FLG mutations can act as a modifying factor in numerous disorders, particularly in those related to abnormalities of keratinization and of the skin barrier.21

Filaggrin is an essential protein for the correct formation and function of the skin barrier. Mutations in the FLG gene are responsible for ichthyosis vulgaris and are associated with a higher risk of developing AD, asthma, allergic rhinitis, and food allergy. The discovery of its function has enabled us to better understand the pathogenesis of various disorders associated with alterations of the skin barrier, and it is likely that its mutations influence the onset or clinical severity of other dermatologic diseases. In addition, the study of its functions and of the consequences of its deficit may have important therapeutic implications in the future, with the possibility of developing new specific treatments for disorders in which this gene is altered.

The authors declare that they have no conflicts of interest.