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Heritable Filaggrin Disorders: the Paradigm of Atopic Dermatitis W.H

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Heritable Filaggrin Disorders: the Paradigm of Atopic Dermatitis W.H View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector GENETICS OF STRUCTURAL SKIN DISORDERS Heritable Filaggrin Disorders: The Paradigm of Atopic Dermatitis W.H. Irwin McLean1 and Alan D. Irvine2,3,4 1Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK; 2National Children’s Research Centre, Dublin, Ireland; 3Department of Paediatric Dermatology, Our Lady’s Children’s Hospital, Dublin, Ireland and 4Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland Correspondence: W.H. Irwin McLean, E-mail: [email protected]; Alan D. Irvine, E-mail: [email protected] doi:10.1038/skinbio.2012.6 THE PROFILAGGRIN/FILAGGRIN PROTEIN the identification of this protein in the tute most of the total mutations (Chen Mutations in the filaggrin gene (FLG) late 1970s (Dale, 1977), its role in et al., 2011). are one of the most common patho- keratin filament aggregation was ra- Once the molecular genetics had genic single-gene defects identified to pidly established (Dale et al., 1978). been established, rapid genotyping of date. FLG encodes an important epi- Some 7 years later, the first evidence large patient collections was possible dermal protein abundantly expressed in that filaggrin was of potential causal and the association with AD was esta- the outer layers of the epidermis (Sandi- interest in ichthyosis vulgaris (IV) blished initially in small collections of lands et al., 2009). Approximately 10% emerged (Sybert et al., 1985). It was Irish children with AD and in Scottish of individuals of European ancestry are to take a further two decades to fully children with AD and asthma (Palmer heterozygous carriers of a loss-of-func- disclose the molecular genetics of IV. et al., 2006). These findings have since tion mutation in FLG resulting in a 50% That delay was due, in large part, to the been replicated many times in varying reduction in expressed protein (Irvine technical difficulty of sequencing this disease collections and population and McLean, 2006). highly repetitive gene and also due to cohorts; the association is one of As a protein, filaggrin is an unusual the confusing inheritance of IV, which the strongest between any gene and beast in biology. It is expressed as a it transpired, which was best explained a complex disease (Rodriguez et al., giant, inactive, polymeric protein, pro- by semi-dominant Mendelian inheri- 2009). Further analysis of additional filaggrin, which is a major constituent tance, rather than by traditionally disease and population collections of keratohyalin granules. At the inter- understood dominant or recessive in- revealed that AD associated with FLG face between the outermost granular heritance (Smith et al., 2006). mutations is, in general, more severe, layer keratinocytes and the stratum Once Smith et al. (2006) had more persistent, more ‘atopic’, more corneum, this proprotein is cleaved cracked the technical aspects of likely to be associated with asthma, into several identical filaggrin subunits. sequencing FLG in carefully chosen and more likely to have herpes infec- It has been postulated that these clinical pedigrees, the first two recur- tions (Irvine et al., 2011). Overall, monomers condense the cytoskeleton rent loss-of-function mutations (R501X collections of AD show a prevalence and contribute to squame formation. In and 2282del4) were identified. Identi- of FLG mutations of between 20 and the cornified layers per se, filaggrin fication of further recurrent mutations 50% (Irvine, 2007). In addition, FLG undergoes further posttranslational swiftly followed (Sandilands et al., mutations are associated with peanut modifications and is ultimately proteo- 2007). Surprisingly, these mutations allergy (Brown et al., 2011). The totality lyzed into a hygroscopic pool of amino proved to be prevalent in European of the contribution of filaggrin to hu- B acids and chemical derivatives thereof, populations, with 9% of these man disease is not limited to low termed natural moisturizing factor populations carrying at least one FLG prevalence loss-of-function mutations, (NMF). Thus, filaggrin has a central mutation (Irvine et al., 2011). An ethno- as more prevalent intragenic copy role in the biogenesis and subsequent specific mutation profile was seen with number mutations also contribute sub- hydration of the stratum corneum population-specific mutation spectra stantially to risk, with the total filaggrin (Irvine et al., 2011). reported in well-studied populations repeat number (the filaggrin index) such as the Singapore Chinese (Chen significantly predicting AD risk with a et al., 2011). In this population, multi- lower odds ratio but a higher frequency DISEASE ASSOCIATIONS ple very low-frequency mutations col- and therefore a significant overall The identification of an association of lectively contribute to the overall total, contribution to disease in addition to filaggrin with atopic dermatitis (AD) compared with the Irish population the lower frequency null alleles (Brown was a slow burning one. Shortly after where five recurrent mutations consti- et al., 2012). E20 NOVEMBER 2012 MILESTONES | CUTANEOUS BIOLOGY THE ROLE OF FILAGGRIN IN been shown to be regulated by envir- Irvine AD, McLean WH, Leung DY (2011) EPIDERMAL BARRIER FUNCTION onmental humidity (Katagiri et al., Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365:1315–27. 2003) indicates that there are signaling The filaggrin story placed a primary Jungersted JM, Scheer H, Mempel M et al. epidermal barrier defect firmly in the pathways in the skin that actively (2010) Stratum corneum lipids, skin barrier forefront of AD pathogenesis and has control filaggrin expression and skin function and filaggrin mutations in patients with led to multiple avenues of inquiry to barrier homeostasis in general. These atopic eczema. Allergy 65:911–8. elucidate early pathogenic pathways are tractable problems that will lead to Katagiri C, Sato J, Nomura J et al. (2003) specific therapeutic approaches once Changes in environmental humidity affect the in AD. The flaky tail mouse, a double water-holding property of the stratum corneum mutant for murine Flg and the matted these pathways are fully understood and its free amino acid content, and the expres- gene (ma), shows a primary epidermal and targeted pharmacologically. sion of filaggrin in the epidermis of hairless mice. barrier defect compounded massively J Dermatol Sci 31:29–35. by allergic inflammation (Fallon et al., CONFLICT OF INTEREST Kezic S, Kemperman PM, Koster ES et al. (2008) The authors state no conflict of interest. Loss-of-function mutations in the filaggrin gene 2009) findings consistent with ex vivo lead to reduced level of natural moisturizing studies that show evidence for modula- factor in the stratum corneum. J Invest Dermatol tion of filaggrin expression by the Th2 TO CITE THIS ARTICLE 128:2117–9. McLean WHI and Irvine AD (2012) Heritable Kezic S, O’Regan GM, Lutter R et al. (2012) cytokines, IL-13 and IL-4 (Howell et al., filaggrin disorders: the paradigm of atopic derma- 2007). Furthermore, filaggrin may have Filaggrin loss-of-function mutations are asso- titis. J Invest Dermatol 132: E20–E21 ciated with enhanced expression of IL-1 cyto- pleiotropic effects on multiple path- kines in the stratum corneum of patients ways relevant to the pathogenesis of with atopic dermatitis and in a murine model of AD including on the growth of Staphy- REFERENCES filaggrin deficiency. J Allergy Clin Immunol 129:1031–9e1. locccus aureus (Miajlovic et al., 2010), Brown SJ, Asai Y, Cordell HJ et al. (2011) Loss- Kezic S, O’Regan GM, Yau N et al. (2011) Levels of-function variants in the filaggrin gene are a skin pH (Jungersted et al., 2010), lipid of filaggrin degradation products are influenced significant risk factor for peanut allergy. J Allergy lamellae secretion and stratum cor- by both filaggrin genotype and atopic dermatitis Clin Immunol 127:661–7. neum structure (Gruber et al., 2011), severity. Allergy 66:934–40. Brown SJ, Kroboth K, Sandilands A et al. (2012) and the expression of pro-inflammatory Miajlovic H, Fallon PG, Irvine AD et al. (2010) Intragenic copy number variation within filaggrin Effect of filaggrin breakdown products on growth cytokines (Kezic et al., 2012). FLG-null contributes to the risk of atopic dermatitis with a of and protein expression by Staphylococcus dose-dependent effect. J Invest Dermatol alleles lead directly to decreased stra- aureus. J Allergy Clin Immunol 126:1184–90e3. 132:98–104. tum corneum NMF (Kezic et al., 2008); O’Regan GM, Kemperman PM, Sandilands A Chen H, Common JE, Haines RL et al. (2011) careful assessment of these levels de- et al. (2010) Raman profiles of the stratum Wide spectrum of filaggrin-null mutations in corneum define 3 filaggrin genotype-determined monstrates three separate subpopula- atopic dermatitis highlights differences between atopic dermatitis endophenotypes. J Allergy Clin tions of AD based on FLG genotype, Singaporean Chinese and European populations. Immunol 126:574–80e1. viz FLG þ / þ , FLG þ /À, and FLGÀ/À Br J Dermatol 165:106–14. Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Dale BA (1977) Purification and characterization (O’Regan et al., 2010). (2006) Common loss-of-function variants of the of a basic protein from the stratum corneum of epidermal barrier protein filaggrin are a major mammalian epidermis. Biochimica Et Biophysica THERAPEUTIC TARGETS predisposing factor for atopic dermatitis. Nat Acta 491:193–204. Genet 38:441–6. Filaggrin expression is downregulated Dale BA, Holbrook KA, Steinert PM (1978) Rodriguez E, Baurecht H, Herberich E et al. (2009) Assembly of stratum corneum basic protein in all cases of moderate-to-severe Meta-analysis of filaggrin polymorphisms in ecze- and keratin filaments in macrofibrils. Nature AD (Kezic et al., 2011), making it an ma and asthma: robust risk factors in atopic 276:729–31. appropriate therapeutic target for AD disease.
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