Filaggrin Gene Defects and the Risk of Developing Allergic Disorders
Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and have been shown to be major predisposing factors for atopic dermatitis (AD). Approximately 40 loss-of-function FLG mutations have been identified in patients with ichthyosis vulgaris (IV) and/or atopic dermatitis (AD) in Europe and Asia. Major differences exist in the spectra of FLG mutations observed between different ancestral groups. Notably, prevalent FLG mutations are distinct between European and Asian populations. Many cohort studies on FLG mutations in AD have revealed that approximately 25-50% of AD patients harbour filaggrin mutations as a predisposing factor. In addition, FLG mutations are significantly associated with AD-associated asthma. The risk for developing allergic rhinitis is also significantly higher with a FLG mutation, both with and without accompanying AD. Recent studies have hypothesized that skin barrier defects caused by FLG mutations allows allergens to penetrate the epidermis and to interact with antigen-presenting cells, leading to the development of atopic disorders including asthma. The restoration of skin barrier function seems a feasible and promising strategy for prophylactic treatment of AD patients with FLG mutations.
allergic rhinitis, asthma, atopic dermatitis, atopic eczema, filaggrin, FLG, ichthyosis vulgaris
Received: 22 September 2010.
Allergology International 2011; 60: 1-9
Filaggrin, which is processed from profilaggrin, is a key protein that facilitates terminal differentiation of the epidermis and formation of the protective skin barrier. In the outer granular layer of the epidermis, filaggrin is associated with keratin intermediate filaments and it aids their packing into bundles. In terminally differentiated keratinocytes, filaggrin is crosslinked to the cornified cell envelope, which constitutes an insoluble barrier in the stratum corneum, protecting the organism against environmental agents and preventing epidermal water loss.1 Mutations in the filaggrin gene (FLG, GenBank accession number NM_002016) have been identified as the underlying cause of the relatively common genetic keratinization disorder ichthyosis vulgaris (IV; OMIM 146700), which is clinically characterized by scaling, especially on the extensor limbs, and by palmoplantar hyperlinearity.2-4 Although FLG is very difficult to analyse because of its large size (>12 kb) and highly repetitive nature, a polymerase chain reaction (PCR) strategy that permits routine and comprehensive sequencing of the entire coding region has recently been developed.5 Until now, around 40 FLG mutations have been reported, and the prevalent FLG mutations are distinct in each population.6 Based on the information of population-specific FLG mutations, many cohort studies on FLG mutations in atopic dermatitis (AD) have been performed and approximately 25-50% of patients with AD were revealed to harbour FLG mutations as a predisposing factor.7 In several studies, these mutations also demonstrated strong association with other allergic phenotypes, including asthma and allergic rhinitis.8 This article gives an overview of FLG population genetics with respect to AD, asthma and allergic rhinitis.
The skin serves numerous functions, the most obvious being its primary protective or barrier function. The large surface area of the skin puts it in constant contact with environmental pollutants, irritants, and allergens, and the horny layer of skin forms the major protective barrier between the body and the environment.
The terminal differentiation of keratinocytes (Fig. 1) results in the formation of an impenetrable barrier (the horny layer) that is the uppermost layer of the epidermis. The successive stages of keratinocytic differentiation in the epidermal layers are the basal cell, spinous cell, and granular cell layers. When spinous cells differentiate into granular cells, they begin to accumulate keratinocyte-specific proteins involved in terminal differentiation of the horny layer.
The skin barrier of the horny layer shows three key features: (i) intercellular lipid layers, (ii) the cornified cell envelope and (iii) the keratin filament network and keratohyaline granules.9 Genetic defects in these components may result in various cutaneous disorders, such as ichthyosis, which is characterized by dry, thickened, scaly or flaky skin. The word "ichthyosis" is from the Ancient Greek, ichthys, meaning "fish".
The keratin filament network is an important basic structure for maintaining the integrity and dimensions of the cornified cell, and the degraded products of the keratohyalin granules, filaggrins, aggregate the keratin filaments in apoptosed keratinocytes into bundles and promote the flattening of dead-cell remnants.10-13
Abnormalities in the barrier function of the horny layer have been hypothesized as permitting epicutaneous allergen exposure in atopic and asthmatic patients. Furthermore, these alterations may, in part, help to explain the recent dramatic increase in atopic and asthmatic disorders in humans living in industrialized nations.
FILAGGRIN EXPRESSION AND FUNCTION
The term 'filaggrin' is derived from filament aggregation protein. A giant inactive precursor, profilaggrin is a large, complex, highly phosphorylated polypeptide that is the main constituent of the keratohyalin granules that are visible in the granular cell layer of the epidermis (Fig. 1). The profilaggrin/filaggrin gene (FLG) resides on chromosome 1q21 and consists of three exons (Fig. 2). Exon 3 is extremely large (>12 kb) and encodes most of the profilaggrin polypeptides with almost completely homologous 10, 11 or 12 repeats. Filaggrin is initially synthesized as profilaggrin, a >400-kDa, highly phosphorylated, histidine-rich polypeptide that comprises an S100 calcium-binding domain, a B-domain and two imperfect filaggrin-repeat domains flanking 10 to 12 essentially identical filaggrin repeats, as well as a C-terminal domain (Fig. 2).14, 15 On terminal differentiation of keratinocytes, profilaggrin is dephosphorylated and cleaved into 10 to 12 essentially identical 37-kd filaggrin peptides. As mentioned above, the liberated filaggrin subsequently and highly efficiently aggregates the keratin filament, which causes the keratinocytes to collapse in the stratum corneum.10, 13 The collapsed crytoskeleton is crosslinked by transglutaminases to bind it to the cornified cell envelope. Filaggrin is subsequently degraded into amino acids that act to retain epidermal moisture.13, 16 Thus, filaggrin is a key protein during terminal differentiation and it is essential for the formation of a normal, intact, protective, and correctly moisturized skin barrier.9, 13
FILAGGRIN DEFICIENCY CAUSED BY FLG
MUTATIONS RESULTS IN ICHTHYOSIS VULGARIS (IV)
IV (OMIM 146700) is a common semidominant inherited skin disorder, estimated to affect 1 in 250 individuals. The onset is early childhood. It is characterized by generalized dry and scaly skin prominent on the extensor surfaces of limbs and on the lower abdomen, and it is associated with palmoplantar hyperlinearity (Fig. 3a, b).2, 17 The symptoms subside during the summer and aggravate during the winter, when the skin tends to dry. Histologically, a decrease in the size and number, or a complete absence, of keratohyalin granules in the epidermis is characteristic of IV. (Fig. 3c-f).2, 18 An association between IV and profilaggrin has long been suspected, but the gene that encodes profilaggrin, FLG, proved technically challenging to sequence. FLG resides on human chromosome 1q21 within the so-called epidermal-differentiation complex (EDC). The EDC is a dense cluster of genes involved in the terminal differentiation of the epidermis and the formation of the stratum corneum, the outermost dead cell compartment of the skin, where the main skin barrier function resides.
The initiation codon of the FLG gene is located in exon 2, although the bulk of the profilaggrin polyprotein in encoded by exon 3 (Fig. 2). Sequencing of exon 3 is problematic, not only because of its size (>12 kb) but also because it consists of between 10 and 12 tandemly arranged filaggrin repeat units. Some individuals have duplication of the 8th and/or 10th domain. The huge size, polymorphic variations in the number of filaggrin repeats, and highly repetitive nature prevent sequencing of the entire gene. Despite these difficulties, the improvement of PCR strategy by the use of long-range sequencing and multiple alignment techniques that permit comprehensive sequencing of the entire FLG gene have recently been developed.14, 17 In 2006, two null mutations, R501X and 2282del4, in the FLG gene were first identified in patients with moderate or severe IV in 15 kindreds from Scottish, Irish, and European-American populations.17 To date, approximately 40 loss-of-function FLG mutations have been identified in IV and/or AD in European populations and Asian populations (Fig. 4).6, 19 In addition, IV was found to exhibit semidominance, with incomplete penetrance (-90% in homozygotes). The homozygotes or compound heterozygotes had a severe form of IV, while the heterozygotes displayed mild or no phenotype.
The genotype/phenotype correlation in FLG mutations has not been clarified. FLG truncation mutations at any site within the profilaggrin peptide were reported uniformly to result in severe deficiency of profilaggrin/filaggrin processing.14 Currently, it has been hypothesized that the profilaggrin C-terminal region is essential for proper processing of profilaggrin to filaggrin and, eventually, truncation at any site of profilaggrin results in abolishment of filaggrin/profilaggrin peptides. The hypothesis is supported by the finding of the nonsense mutation K4022X in the C-terminal incomplete filaggrin repeat. In the epidermis of patients carrying this mutation, profilaggrin/filaggrin peptides were remarkably reduced, even though FLG mRNA expression was not reduced significantly and the expressed mRNA included messages derived from both the wild-type alleles and the mutant alleles.20 Histopathologically, however, the size of keratohyaline granules in the granular layers was decreased and immunohistochemically profilaggrin/filaggrin peptides were remarkably reduced in the patients' epidermis. These observations further support the hypothesis that the profilaggrin C-terminal region is essential for proper profilaggrin processing. It is now generally considered that all the truncation mutations lead to serious loss of filaggrin peptides, resulting in the absence of genotype/phenotype correlations with regard to FLG mutations in IV and AD.
PREVALENT FILAGGRIN MUTATIONS ARE DISTINCT IN EACH RACE
To date, approximately 40 loss-of-function FLG mutations have been identified in IV and/or AD in European populations and Asian populations (Fig. 4).6, 19 Mutations in FLG were initially identified in European families.17, 21, 22 To establish baseline FLG mutation data for the Japanese population, we performed FLG mutation searches in more than 30 Japanese families with IV, after sequencing methods for the entire FLG coding region had been established. We carried out comprehensive sequencing of the entire FLG coding region using an overlapping PCR strategy and identified four Japanese-population-specific mutations in FLG: 3321delA, S2554X, S2889X, and S3296X.23, 24 In 2009, we reported two additional novel FLG mutations, S1695X and Q1701X, in the Japanese population.25 Furthermore, we studied 19 newly recruited Japanese patients with AD and identified a novel FLG nonsense mutation, K4022X, in one patient with AD without any other known Japanese FLG mutation.20 In addition, one of the common European mutations, R501X, was reported in a Japanese family.26 The study was repeated in other Asian populations, including Chinese,27 Taiwanese28 and Korean populations.29 Only two identical mutations (R501X and E2422X) were reported in both European and Asian populations.26, 27 Further haplotype analysis of the European-specific mutation R501X in the Japanese family showed that the mutation was not inherited from an European ancestor but occurred de novo in Japan.26 Among Asian populations, 3321delA was found in all four East Asian populations23, 26-29 and Q2417X was reported in Chinese and Taiwanese populations.27, 28 These results have revealed the differences in filaggrin population genetics between Europe and Asia (Fig. 4). As mentioned above, most FLG mutations are specific to a population, such as Europeans, Japanese, Singaporeans, Chinese, and Taiwanese. Major differences exist in the spectra of FLG mutations observed between different ancestral groups. Prevalent FLG mutations are distinct in both the European and the Asian populations. In addition, there is a need to assess the ancestral admixture in geographical regions in order to know precisely the spectrum and preferential occurrence of FLG mutations in different populations. Every population is likely to have a unique set of FLG mutations. For mutation screening, we have to obtain information on prevalent FLG mutations in each population.
FILAGGRIN MUTATIONS CONFER STRONG GENETIC SUSCEPTIBILITY TO ATOPIC DERMATITIS
AD, one of the most common skin disorders, affects 15-20% of children in the developed world. AD often presents with IV. AD is a pruritic skin disease that typically starts early in life. The onset is during the first 6 months of life in 45% of affected individuals, the first year of life in 60% of affected individuals, and before 5 years of age in at least 85% of affected individuals.30 The hallmark of the disease is a pruritic dermatitis that localizes in different areas depending on age. In infancy it tends to affect the face and extensors of the lower legs, and in childhood the flexural areas; in adulthood the eruption has a more diffuse distribution. Other important diagnostic indications include xerosis of the skin, early age of onset, and a chronic, relapsing course. The incidence and prevalence of AD decreases with increasing age. AD is thought to have various heterogeneous etiologic factors, including genetic predisposing factors and environmental factors. Despite considerable efforts to elucidate genes that confer susceptibility to AD and to clarify the genetic background of atopic disorders, until recently no strong and reproducible genetic factor has been identified.31 Transepidermal water loss (TEWL) and SC hydration, which are measurements of skin barrier function, were reported to be increased in AD patients due to their skin barrier insufficiency.32 Significant correlations were observed between penetration rates of a hydrophilic dye and elevated IgE levels in patients with severe AD.33 In addition, percutaneous penetration of sodium lauryl sulphate was reported to be increased in uninvolved skin of patients with AD.34 Taken together, these findings strongly support the hypothesis that patients with AD have a skin barrier defect. Three clues suggested that FLG mutations play an important role in AD pathogenesis. First, dermatologists have recognized that AD often occurs in patient with IV, although the pathophysiological mechanisms of this co-occurrence have not been fully clarified.35-37 Second, the linkage of AD to the chromosome locus on 1q21, which contains the epidermal differentiation complex where FLG resides, has been reported.38 Third, decreased filaggrin expression has been reported in the skin of patients with AD at both the mRNA and the protein levels.39, 40
Palmer et al. first reported that decreased or absent FLG expression due to loss-of-function mutations leads to impaired barrier function which manifests as AD.21 They found that AD was manifested in heterozygous carriers of two null FLG mutations, R501X and 2282del4, with a relative risk (odds ratio) for AD of 13.4, implying a causal relationship. Thereafter, about twenty case-control analyses and eight familial analyses investigated the association between filaggrin gene defects and AD. Most of the studies were on Western European populations, but three case-control studies and one family study were on a Japanese population and one case-control study was on a North American population.14, 41-47 In the Japanese population, there are at least eight FLG mutations. We showed that about 27% of the patients in our Japanese AD case series carried one or more of these eight FLG mutations (OR: 9.94; 95%; CI: 3.77-26.2) and that these variants were also carried by 3.7% of the Japanese general control individuals.20 Meta-analysis FLG mutation studies on AD, focusing on the European-prevalent mutations (R501X or 2282del4) found an overall OR of 4.78 (95%; CI: 3.31-6.92) from the case-control studies and a summary OR of 1.99 (95%; CI: 1.72-2.31) from the family studies.8 The strong association between FLG mutations and AD marked a milestone in the genetic study of complex allergic disorders. It was confirmed that the strong effect of FLG mutations on AD risk exceeds that of any other candidate predisposing gene for AD identified so far. Based on the information of population-specific FLG mutations, many cohort studies of AD for FLG mutations were performed and approximately 25-50% of AD patients were revealed to harbour FLG mutations as a predisposing factor.6
As mentioned above, every population is likely to have a unique set of FLG mutations. Population differences highlighted by FLG mutations make it difficult to perform worldwide screening for FLG mutations in patients with AD. We cannot perform FLG mutation screening in one population using the FLG mutations reported in other populations. For example, we cannot use the prevalent European FLG mutations when we screen Asian patients with AE. For mutation screening, we have to obtain information on prevalent FLG mutations in each population. It is therefore important to establish global population genetic maps for FLG mutations.
MUTATIONS AND ASTHMA
The clinical cause of atopic disorders has been described as an atopic or allergic march. It involves sensitisation to food or aeroallergens, or both, in early life, progressing to eczema and wheezing within the first two years of life, and often leading to chronic asthma, rhinitis, and other clinical manifestations of atopic allergy in later life. Previous studies showed that 70% of patients with severe AD developed asthma, compared with 30% of patients with mild AD, and approximately 8% of the general population.48 Previous studies in European populations have reported that variants in the FLG gene are associated with eczema and concomitant asthma41-45 or with eczema alone.22 One recent meta-analysis study showed that FLG mutations are significantly associated with asthma (OR: 1.48; 95%; CI, 1.32-1.66). And strong effects for the compound phenotype of asthma plus eczema (OR: 3.29; 95%; CI, 2.84-3.82) were observed. In contrast, FLG mutations did not seem to be associated with asthma in the absence of eczema (OR: 1.11; 95%; CI: 0.88-1.41).49
To clarify whether FLG mutations are a predisposing factor for asthma in non-European populations, we studied 172 Japanese AE patients, 137 Japanese asthma patients and 134 unrelated Japanese control individuals. There is a statistically significant association between the eight FLG mutations and AE with asthma, and between the eight FLG mutations and AE without asthma. In the Japanese general asthma cohort, there was a statistically significant association between the eight FLG mutations and asthma with AE. There was no statistically significant association between the FLG mutations and overall asthma patients, nor between FLG mutations and asthma without AE. This Japanese cohort has a completely different FLG mutation spectrum from those in the European and the North American populations. However, our results clearly confirm the strong association of FLG mutations with our Japanese cohort of AE patients with asthma complications, and the association of FLG mutations and asthma patients with AE complications.50
The mechanism of the asthma risk associated with FLG null alleles is not yet fully understood. FLG is expressed in the skin and in the outer layers of the oral and nasal mucosae, but not in the respiratory epithelium of the nose or the lower airways.51, 52 Therefore it has been suggested that FLG-associated asthma is mediated by percutaneous priming53 and/or secondary, possibly systemic, immunologic mechanisms stimulated through the impaired skin barrier. Recent studies hypothesized that skin barrier defects caused by FLG mutations allow allergens to penetrate the epidermis and to interact with antigen-presenting cells (Langerhans cells and dermal dendritic cells, which might further initiate Th2 immune response and lead to the development of atopic disorders including AD, asthma and allergic rhinitis.53, 54
FILAGGRIN MUTATIONS AND ALLERGIC RHINITIS
Three case-control studies investigated the association between filaggrin gene defects and the risk of developing allergic rhinitis in people without AD.42, 55, 56 Recent meta-analysis study showed that FLG mutations are significantly associated with allergic rhinitis without AD (OR: 1.78; 95%; CI: 1.16-2.73). In addition, the FLG mutations are significantly associated with allergic rhinitis with AD (OR: 2.84; 95%; CI: 2.08-3.88).8 Filaggrin is expressed in the anterior vestibulum of the nose, but not in transitional and respiratory nasal epithelia.56 Thus, it seems unlikely that FLG mutations exert organ-specific and localized effects in the upper airways. The mechanisms through which FLG mutations contribute to airway disease are not understood yet. Percutaneous priming and secondary immunologic effects from the induction of Th2 cytokines in epithelia are interesting hypotheses that need further investigation.
NOVEL TREATMENT FOR AD BASED ON RECENT FLG
The epidermal barrier dysfunction caused by FLG mutations has been recognized as a major contributor to the pathogenesis of AD over the past few years. The skin barrier defect is the primary event that initiates disease pathogenesis, allowing the entrance of numerous antigens into the epidermis in patients with AD. Thus, the restoration of skin barrier function seems a feasible and promising strategy for prophylactic treatment of AD patients with FLG mutation. There have been efficient clinical methods to restore skin barrier function, including the application of general moisturizers and specific lipid replacement therapy.57 When used under nursing supervision, moisturizers have been shown to reduce topical steroid usage.58 In addition, the topical application of ceramide-dominant lipid replacement therapy was proved effective in alleviating skin barrier defects and reducing AD severity significantly in childhood AD patients.59
Regarding the association between filaggrin deficiency and sensitization to specific antigens, allergen exposure during early life may increase the risk of AE, but the protective effect of reduction in allergen exposure remains uncertain. According to a population-based, longitudinal birth cohort study by Henderson et al., eczema associated with FLG mutations presents in early life and is persistent.60 In addition, a strong association was identified between FLG mutations and sensitisation to grass, house dust, mites, and cat dander. Our study revealed that AD disease severity and specific IgE for house dust, mite allergen, and cat dander were significantly correlated in FLG mutation-related patients with AD.61 In light of this, if we select patients with FLG mutations and perform early intervention to reinforce/improve their skin barrier function and reduce sensitization to allergens, we may achieve a significant prophylactic effect against AD development. Further studies are required to clarify the preventive effect of early intervention against AD in high-risk, filaggrin-deficient children.
This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan to M. Akiyama (Kiban B).
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