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• W2087256989 abstract "atopic dermatitis human filaggrin-encoding gene natural moisturizing factor stratum corneum To the Editor Filaggrin is a key protein required for the formation of the stratum corneum (SC) barrier. Filaggrin is also essential for SC hydration, as it acts as a source of hygroscopic amino acids and their derivatives, known as natural moisturizing factor (NMF). The human gene encoding filaggrin (FLG) is highly polymorphic and to date, 15 null mutations have been detected of which four (R501X, 2282del4, R2447X, and S3247X) are prevalent at varying frequencies in the white European population (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O’Regan G.M. Clayton T.H. Watson R.M. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (474) Google Scholar). Homozygous or compound heterozygous FLG mutations underlie the common skin-keratinizing disorder ichthyosis vulgaris, and have been shown to be a major genetic predisposing factor for atopic dermatitis (AD) (Sandilands et al., 2006Sandilands A. O’Regan G.M. Liao H. Zhao Y. Terron-Kwiatkowski A. Watson R.M. et al.Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.J Invest Dermatol. 2006; 126: 1770-1775Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Diminished filaggrin expression has been demonstrated in both ichthyosis vulgaris and AD skin (Seguchi et al., 1996Seguchi T. Cui C.Y. Kusuda S. Takahashi M. Aisu K. Tezuka T. Decreased expression of filaggrin in atopic skin.Arch Dermatol Res. 1996; 288: 442-446Crossref PubMed Scopus (147) Google Scholar; Sugiura et al., 2005Sugiura H. Ebise H. Tazawa T. Tanaka K. Sugiura Y. Uehara M. et al.Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope.Br J Dermatol. 2005; 152: 146-149Crossref PubMed Scopus (137) Google Scholar; Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. Sandilands A. Campbell L.E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (755) Google Scholar). As filaggrin is the precursor protein for the amino-acid-derived components of the NMF, we hypothesized that carriers of FLG-null mutations have reduced level of NMF in the SC. To measure NMF in the SC of the palm (thenar eminence) and forearm skin, we used confocal Raman microspectroscopy (3510 Skin Composition Analyzer; River Diagnostics, Rotterdam, The Netherlands). The principles of this method and the procedure have extensively been described elsewhere (Caspers et al., 2001Caspers P.J. Lucassen G.W. Carter E.A. Bruining H.A. Puppels G.J. In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles.J Invest Dermatol. 2001; 116: 434-442Crossref PubMed Scopus (660) Google Scholar, Caspers et al., 2003Caspers P.J. Lucassen G.W. Puppels G.J. Combined in vivo confocal Raman spectroscopy and confocal microscopy of human skin.Biophys J. 2003; 85: 572-580Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar). The reference spectrum of NMF was constructed from a superposition of the spectra of pyrrolidone-5-carboxylic acid, ornithine, serine, proline, glycine, histidine, and alanine. In addition to NMF, skin barrier function as measured by transepidermal water loss was assessed on the volar forearm (Tewameter 210; Courage and Khazaka Electronic GmbH, Cologne, Germany). One hundred and forty-nine volunteers recruited by public advertisement, as well as 10 AD patients, were screened for four FLG mutations (R501X, 2282del4 R2447X, and S3247X). All subjects filled in a questionnaire on the history of skin diseases and allergies, and the Erlangen atopy questionnaire that also included a question on skin dryness. Signs of active disease (erythema, crusting, weeping, and lichenification) were assessed by a dermatologist. Having visible skin changes on the forearm was the exclusion criterion. Written informed consent was obtained from all subjects. The experimental protocol followed the Declaration of Helsinki Principles and was approved by the Ethical Committee of the Academic Medical Centre. Genomic DNA was extracted from buccal swab samples (Puregene® DNA isolation kit; Gentra Systems, Minneapolis, MN). Polymorphisms were genotyped as reported previously (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O’Regan G.M. Clayton T.H. Watson R.M. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (474) Google Scholar). To compare data from two groups, we used two-tailed Student's t-test for unpaired samples. Sixteen carriers (12 female) of an FLG mutation and 23 individuals (15 female) wild type with respect to these mutations were included in the study. Of the 16 carriers, five were heterozygous for R501X, eight were heterozygous for 2282del4, and one was heterozygous for R2447X. One individual was homozygous for 2282del4 and one individual was compound heterozygous for R501X and 2282del4. The mean age of the carrier group was 33 years (range 20–55 years), which was comparable with that of non-carriers (mean 30, range 20–61 years). The prevalence of AD history and active AD was higher in carriers of an FLG mutation (Figure 1). Further, all carriers and 11 non-carriers reported having a dry skin. In this study, we have demonstrated that individuals who are carriers of FLG-null mutations have significantly reduced levels of NMF in the SC on both skin locations and at all SC depths (Figures 1 and 2). Palmar skin showed less interindividual differences in NMF levels as compared with forearm skin (Figure 1). FLG carriers who had signs of active disease (n=4) did not have NMF values different from those in individuals without active AD (both skin locations P>0.1), although we acknowledge that the size of groups are small. Also a history of AD did not result in different NMF levels within both groups (P>0.1). Furthermore, FLG carriers with a history of AD had significantly lower NMF level than non-carriers with a history of AD (P<0.0001). Two individuals who were homozygous and compound heterozygous for investigated FLG mutations showed lower NMF levels than the group averages (Figure 1). Although clear difference was found in NMF content between carriers and non-carriers of FLG mutations, it has to be realized that NMF content is dependent on several factors and not only on the FLG genotype (Rawlings and Matts, 2005Rawlings A.V. Matts P.J. Stratum corneum moisturization at the molecular level: an update in relation to dry skin cycle.J Invest Dermatol. 2005; 124: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). The breakdown of filaggrin is under control of proteolytic enzymes and is influenced by the hydration gradient across the skin that is dependent on the external humidity and the transepidermal water loss. The latter factor is influenced by the quality of the skin barrier, primarily by the composition and structure of the lipid bilayers. There are also other possible genetic modifiers of the effect of FLG mutations, which are plausibly involved in controlling filaggrin processing, including SPINK5 and SCCE (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O’Regan G.M. Clayton T.H. Watson R.M. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (474) Google Scholar). In addition, a heterozygote for a loss-of-function mutation might carry an expanded exon 3 on the other allele, lessening the overall effect of the mutation (Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. Sandilands A. Campbell L.E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (755) Google Scholar). Furthermore, it has recently been reported that filaggrin skin expression could be modulated by the atopic inflammatory response mediated by cytokines IL-4 and IL-13 (Howell et al., 2007Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2007; 120: 150-155Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar). In addition to reduced levels of NMF, carriers of FLG mutations showed a higher transepidermal water loss as compared with non-carriers (10.3±2.7 and 8.3±2.2 g hm−2, respectively; P=0.01). The literature data on transepidermal water loss in AD patients is contradictory, and this inconsistency might, at least partly, be explained by different phenotypes of AD patients. Given that approximately 50% of moderate-to-severe AD patients may be carriers of an FLG-null mutation, it has been speculated that FLG status may define a subtype of barrier-related AD. Since polymorphisms in the FLG gene lead to reduced amount of filaggrin and consequently to a decreased level of NMF, measurement of NMF could improve classification of AD phenotypes. Identification of this measurable physical parameter as a marker of FLG status could enable more targeted prevention of AD in susceptible individuals. Measurement of the NMF phenotype in particular by in vivo Raman spectroscopy, is much less demanding then genotyping. This initial study shows some highly promising results. Sensitivity and specificity of this method will be further investigated in larger, well-defined study groups to explore its potential usefulness in clinical practice. Irwin McLean has filed patents relating to genetic testing and therapy development aimed at the filaggrin gene. The other authors state no conflict of interest. Corrigendum: Loss-of-Function Mutations in the Filaggrin Gene Lead to Reduced Level of Natural Moisturizing Factor in the Stratum CorneumJournal of Investigative DermatologyVol. 128Issue 6PreviewCorrection to: Journal of Investigative Dermatology advance online publication, February 28, 2008; doi: 10.1038/jid.2008.29 Full-Text PDF Open Archive" @default.
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