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Atopic Eczema and the Filaggrin Story Sara J

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Atopic Eczema and the Filaggrin Story Sara J Atopic Eczema and the Filaggrin Story Sara J. Brown, MBChB, BSc, MRCP,* and Alan D. Irvine, MD, FRCPI† The discovery that null mutations in the filaggrin gene (FLG) are associated with atopic eczema represents the single most significant breakthrough in understanding the genetic basis of this complex disorder. The association has been replicated in multiple independent studies during the past 2 years with the use of various methodologies, from populations in Europe, the United States, and Japan. Filaggrin plays a key role in epidermal barrier function, and its association with atopic eczema emphasizes the importance of barrier dysfunction in eczema pathogenesis. This review aims to summarize the current state of knowledge regarding the role of FLG mutations in ichthyosis vulgaris, atopic eczema, and other skin disorders, with an emphasis on potential clinical applications. Further research is needed to clarify the precise role of filaggrin in skin and systemic atopic disease, to pave the way for novel therapeutic interventions. Semin Cutan Med Surg 27:128-137 © 2008 Elsevier Inc. All rights reserved. topic eczema1 is a complex disorder, ie, multiple geneticphisms in genes encoding proteins important in the structure A and environmental factors contribute to its2 etiology.and function of the skin, rather than through systemic im- The recent discovery that mutations within the filaggrinmune gene or “atopy” risk genes. Eczema can occur with increased (FLG) are strongly associated with atopic eczema representsseverity a along Blaschko’s 9lines, and this mosaicism further very significant breakthrough in understanding the geneticsupports the concept that skin-specific eczema risk genes basis of this common disorder. Many publications relatingmay beto relevant. Genome-wide linkage 10 andscreens DNA filaggrin have appeared in rapid succession during themicroarray past 2 analysis11 have also indicated a role for genes years and form the basis of this review. expressed locally in the skin and there is a growing under- standing of the importance of epithelial barrier dysfunction Genetic Factors in atopic eczema.12,13 However, many promising preliminary discoveries in the field of eczema genetics have failed to be in Atopy and Eczema replicated in subsequent studies.2 There is substantial evidence in support of a strong In geneticMay 2006, a group led by Professor Irwin McLean (Uni- component in the etiology of atopic eczema. Studies versityin twinsof Dundee, UK) with collaborators in Ireland, Scot- show concordance rates of approximately 0.8 in monozy-land, and Demark, reported that 2 common polymorphisms gotic twin pairs compared with 0.2 in dizygotic twinin thepairs filaggrin FLGgene) (are strong predisposing factors for 14 (that is to say an identical twin has an 80% chanceatopic ofeczema. devel-This finding arose from the study of ichthy- oping eczema if their twin is affected whereas a fraternalosis vulgaris, twin demonstrating that the study of Mendelian dis- 15 has an approximately 20% chance of developing eczemaorders ifcan shed light on complex traits. their twin is affected).3-5 Eczema and other atopic disorders show clustering within families6 and children whose parentsFilaggrin: Basic Science have atopic eczema have a greater risk of developing eczema than children whose parents have asthma or7,8 hay Filaggrinfever. fil(ament-aggregating protein) plays a key role in These observations suggest that the genetic risk of epidermaleczema barrier function. TheFLG gene is encoded within may be mediated through tissue-specific factors, ie, polymor-the epidermal differentiation complex on chromosome 1q21, a cluster of genes involved in the terminal differentiation of keratinocytes.16 In the skin,FLG is expressed in the granular *Royal Victoria Infirmary, Newcastle upon Tyne, UK. layer of the stratum corneum during terminal epidermal dif- †Our Lady’s Children’s Hospital Crumlin, Dublin, Associate Professor of ferentiation. In the gastrointestinal system, FLG is expressed Dermatology, Trinity College, Dublin, Ireland. 17 18 Address reprint requests and correspondence to: Dr Sara Brown, Depart- in the oral and upper esophageal mucosa. In the respira- ment of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, tory system, it is expressed in the cornified epithelium of the UK: NE1 4LP. E-mail: [email protected] nasal vestibulum but not within the transitional epithelium 128 1085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.sder.2008.04.001 Atopic eczema and the filaggrin story 129 Figure 1 Diagrammatic representation of the processing and functions of filaggrin within the epidermis. Filaggrin plays a key role in facilitating epidermal differentiation and maintaining barrier function, but the relative importance of the different functions of filaggrin remains unclear. Filaggrin aggregates the keratin cytoskeleton by organizing interme- diate filaments into tight bundles.21 This facilitates the collapse and flattening of keratinocytes in the outermost skin layer to produce squamous cells. The protein-lipid cornified cell envelope is extensively cross-linked by transglutami- nases and forms an important barrier,22 helping to prevent water loss and minimizing the entry of allergens and micro-organisms. Filaggrin is subsequently deiminated (the positive arginine residues are converted to neutral citrul- line) and degraded to produce a mixture of hygroscopic amino acids, as part of the so-called “natural moisturizing factor,”23 which may also contribute to epidermal barrier function. Finally, the amino-terminal portion (S100 domain) of profilaggrin is a calcium binding domain24 and may therefore play a role in the regulation of calcium-dependent events during epidermal differentiation; conversely, calcium may play a role in the control of profilaggrin processing. Genotypes resulting in relative or absolute filaggrin deficiency may therefore produce epidermal barrier dysfunction by more than one mechanism.25 (Color version of figures is available online.) covering the inferior turbinate bone.19 Filaggrin is not ex- acids in the stratum corneum and increased transepidermal wa- pressed in the respiratory epithelium beyond this point and ter loss.28 specifically it is not expressed in the bronchial mucosa.19,20 FLG encodes a large insoluble polyprotein, profilaggrin, which is the major constituent of keratohyalin granules (Fig. Ichthyosis Vulgaris and 1).21-25 Profilaggrin is proteolytically cleaved to produce 10, 11, Filaggrin or 12 copies of the filaggrin peptide, according to our current understanding of population size polymorphisms.26 Filaggrin Ichthyosis vulgaris (OMIM #146700) is the most common in- aggregates keratin 1, keratin 10, and other intermediate fila- herited disorder of keratinization, with an estimated prevalence ments within the cytoskeleton of keratinocytes, helping to bring of between 1 in 80 and 1 in 250 in English school children.29,30 about their compaction into a squame shape during cornifica- Several convergent lines of reasoning led to study of the filaggrin tion, a unique form of programmed cell death.22 The resultant gene as a cause for ichthyosis vulgaris. Skin histology from pa- cornified cell envelope replaces the keratinocyte cell membrane. tients with ichthyosis vulgaris shows a reduction in keratohyalin It forms an important permeability barrier to water, microbes, granules31,32 and immunostaining shows a reduction in filag- and allergens and provides mechanical defense by maintaining grin31 and profilaggrin mRNA33; genome-wide screens have skin integrity.27 After keratinocyte compaction, filaggrin pro- shown linkage of ichthyosis vulgaris to markers in the epidermal teins are broken down to release hygroscopic amino acids, (part differentiation complex on chromosome 1q2116,34; finally, a of the so-called “natural moisturising factor”), which may also murine model of ichthyosis vulgaris, the flaky-tail mouse, shows contribute to epidermal barrier function by retaining water and, genetic linkage to the mouse epidermal differentiation com- hence, increasing flexibility of the cornified layer. FLG null mu- plex.32 tations are associated with reduced levels of hygroscopic amino These observations date from the 1980s and although the 130 S.J. Brown and A.D. Irvine encodes profilaggrin 10 to 12 repeats 5’ 3’ UTR Exon 1 Exon 2 Exon 3 UTR (159bp) (12,753bp) (15bp) Key: Sequences unique to the FLG gene, encoding a S100 domain (at 5’ end of exon 3), B domain and C terminus (at 3’ end of exon 3) Partial repeat Filaggrin repeat (972 base pairs each) UTR untranslated region Figure 2 Structure of the filaggrin gene (FLG) and its corresponding protein. Modified diagram, from Smith and coworkers32 and Sandilands and coworkers.36,37 FLG is located on chromosome 1q21. Exons 1 and 2 showed no variation between individuals with and without ichthyosis vulgaris in 5 families.32 Exon 2 contains the initiation codon. Exon 3 is unusually large and encodes most of the N-terminal domain as well as all of the filaggrin repeats and their linker sequences. Profilaggrin is polymorphic in that there are three alleles in the human population encoding 10,11 or 12 filaggrin repeats.26 bp, base pairs; UTR, untranslated region. (Color version of figures is available online.) profilaggrin gene was sequenced in 1992,35 the identification vulgaris29 and 37% to 50% of patients with ichthyosis vul- of causative mutations in patients with ichthyosis vulgaris garis have atopic eczema.29,32 Furthermore, because filaggrin was delayed until 2006. This
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