FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2240371028> ?p ?o ?g. }

• W2240371028 endingPage "E21" @default.
• W2240371028 startingPage "E20" @default.
• W2240371028 abstract "Mutations in the filaggrin gene (FLG) are one of the most common pathogenic single-gene defects identified to date. FLG encodes an important epidermal protein abundantly expressed in the outer layers of the epidermis (Sandilands et al., 2009Sandilands A. Sutherland C. Irvine A.D. et al.Filaggrin in the frontline: role in skin barrier function and disease.J Cell Sci. 2009; 122: 1285-1294Crossref PubMed Scopus (558) Google Scholar). Approximately 10% of individuals of European ancestry are heterozygous carriers of a loss-of-function mutation in FLG resulting in a 50% reduction in expressed protein (Irvine and McLean, 2006Irvine A.D. McLean W.H. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis.J Invest Dermatol. 2006; 126: 1200-1202Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). As a protein, filaggrin is an unusual beast in biology. It is expressed as a giant, inactive, polymeric protein, profilaggrin, which is a major constituent of keratohyalin granules. At the interface between the outermost granular layer keratinocytes and the stratum corneum, this proprotein is cleaved into several identical filaggrin subunits. It has been postulated that these monomers condense the cytoskeleton and contribute to squame formation. In the cornified layers per se, filaggrin undergoes further posttranslational modifications and is ultimately proteolyzed into a hygroscopic pool of amino acids and chemical derivatives thereof, termed natural moisturizing factor (NMF). Thus, filaggrin has a central role in the biogenesis and subsequent hydration of the stratum corneum (Irvineet al., 2011). The identification of an association of filaggrin with atopic dermatitis (AD) was a slow burning one. Shortly after the identification of this protein in the late 1970s (Dale, 1977Dale B.A. Purification and characterization of a basic protein from the stratum corneum of mammalian epidermis.Biochimica Et Biophysica Acta. 1977; 491: 193-204Crossref PubMed Scopus (84) Google Scholar), its role in keratin filament aggregation was rapidly established (Dale et al., 1978Dale B.A. Holbrook K.A. Steinert P.M. Assembly of stratum corneum basic protein and keratin filaments in macrofibrils.Nature. 1978; 276: 729-731Crossref PubMed Scopus (196) Google Scholar). Some 7 years later, the first evidence that filaggrin was of potential causal interest in ichthyosis vulgaris (IV) emerged (Sybert et al., 1985Sybert V.P. Dale B.A. Holbrook K.A. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules.J Invest Dermatol. 1985; 84: 191-194Abstract Full Text PDF PubMed Scopus (243) Google Scholar). It was to take a further two decades to fully disclose the molecular genetics of IV. That delay was due, in large part, to the technical difficulty of sequencing this highly repetitive gene and also due to the confusing inheritance of IV, which it transpired, which was best explained by semi-dominant Mendelian inheritance, rather than by traditionally understood dominant or recessive inheritance (Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (808) Google Scholar). Once Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (808) Google Scholar had cracked the technical aspects of sequencing FLG in carefully chosen clinical pedigrees, the first two recurrent loss-of-function mutations (R501X and 2282del4) were identified. Identification of further recurrent mutations swiftly followed (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. 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 (515) Google Scholar). Surprisingly, these mutations proved to be prevalent in European populations, with ~9% of these populations carrying at least one FLG mutation (Irvine et al., 2011Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (834) Google Scholar). An ethno-specific mutation profile was seen with population-specific mutation spectra reported in well-studied populations such as the Singapore Chinese (Chen et al., 2011Chen H. Common J.E. Haines R.L. et al.Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.Br J Dermatol. 2011; 165: 106-114Crossref PubMed Scopus (106) Google Scholar). In this population, multiple very low-frequency mutations collectively contribute to the overall total, compared with the Irish population where five recurrent mutations constitute most of the total mutations (Chen et al., 2011Chen H. Common J.E. Haines R.L. et al.Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.Br J Dermatol. 2011; 165: 106-114Crossref PubMed Scopus (106) Google Scholar). Once the molecular genetics had been established, rapid genotyping of large patient collections was possible and the association with AD was established initially in small collections of Irish children with AD and in Scottish children with AD and asthma (Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. et al.Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet. 2006; 38: 441-446Crossref PubMed Scopus (2274) Google Scholar). These findings have since been replicated many times in varying disease collections and population cohorts; the association is one of the strongest between any gene and a complex disease (Rodriguez et al., 2009Rodriguez E. Baurecht H. Herberich E. et al.Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease.J Allergy Clin Immunol. 2009; 123: 1361e7-1370e7Abstract Full Text Full Text PDF Scopus (336) Google Scholar). Further analysis of additional disease and population collections revealed that AD associated with FLGmutations is, in general, more severe, more persistent, more ‘atopic’, more likely to be associated with asthma, and more likely to have herpes infections (Irvine et al., 2011Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (834) Google Scholar). Overall, collections of AD show a prevalence of FLG mutations of between 20 and 50% (Irvine, 2007Irvine A.D. Fleshing out filaggrin phenotypes.J Invest Dermatol. 2007; 127: 504-507Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). In addition, FLG mutations are associated with peanut allergy (Brown et al., 2011Brown S.J. Asai Y. Cordell H.J. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar). The totality of the contribution of filaggrin to human disease is not limited to low prevalence loss-of-function mutations, as more prevalent intragenic copy number mutations also contribute substantially to risk, with the total filaggrin repeat number (the filaggrin index) significantly predicting AD risk with a lower odds ratio but a higher frequency and therefore a significant overall contribution to disease in addition to the lower frequency null alleles (Brown et al., 2012Brown S.J. Kroboth K. Sandilands A. et al.Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect.J Invest Dermatol. 2012; 132: 98-104Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). The filaggrin story placed a primary epidermal barrier defect firmly in the forefront of AD pathogenesis and has led to multiple avenues of inquiry to elucidate early pathogenic pathways in AD. Theflaky tail mouse, a double mutant for murine Flg and the matted gene (ma), shows a primary epidermal barrier defect compounded massively by allergic inflammation (Fallon et al., 2009Fallon P.G. Sasaki T. Sandilands A. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (376) Google Scholar) findings consistent with ex vivo studies that show evidence for modulation of filaggrin expression by the Th2 cytokines, IL-13 and IL-4 (Howell et al., 2007Howell M.D. Kim B.E. Gao P. 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 (586) Google Scholar). Furthermore, filaggrin may have pleiotropic effects on multiple pathways relevant to the pathogenesis of AD including on the growth of Staphylocccus aureus (Miajlovic et al., 2010Miajlovic H. Fallon P.G. Irvine A.D. et al.Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus.J Allergy Clin Immunol. 2010; 126: 1184e3-1190e3Abstract Full Text Full Text PDF Scopus (158) Google Scholar), skin pH (Jungersted et al., 2010Jungersted J.M. Scheer H. Mempel M. et al.Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema.Allergy. 2010; 65: 911-918Crossref PubMed Scopus (247) Google Scholar), lipid lamellae secretion and stratum corneum structure (Gruber et al., 2011Gruber R. Elias P.M. Crumrine D. et al.Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.Am J Pathol. 2011; 178: 2252-2263Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar), and the expression of pro-inflammatory cytokines (Kezic et al., 2012Kezic S. O’Regan G.M. Lutter R. et al.Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.J Allergy Clin Immunol. 2012; 129: 1031e1-1039e1Abstract Full Text Full Text PDF Scopus (179) Google Scholar). FLG-null alleles lead directly to decreased stratum corneum NMF (Kezic et al., 2008Kezic S. Kemperman P.M. Koster E.S. et al.Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum.J Invest Dermatol. 2008; 128: 2117-2119Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar); careful assessment of these levels demonstrates three separate subpopulations of AD based on FLG genotype, viz FLG +/+, FLG +/–, and FLG–/– (O’Regan et al., 2010O’Regan G.M. Kemperman P.M. Sandilands A. et al.Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes.J Allergy Clin Immunol. 2010; 126: 574e1-580e1Abstract Full Text Full Text PDF Scopus (119) Google Scholar). Filaggrin expression is downregulated in all cases of moderate-to-severe AD (Kezic et al., 2011Kezic S. O’Regan G.M. Yau N. et al.Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (209) Google Scholar), making it an appropriate therapeutic target for AD in the broadest sense, rather than being confined to AD associated with FLG-null alleles. The filaggrin index effect, where a modest 20% increase in filaggrin copy number leads to a 40% reduction in AD susceptibility (Brown et al., 2012Brown S.J. Kroboth K. Sandilands A. et al.Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect.J Invest Dermatol. 2012; 132: 98-104Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), is highly suggestive that filaggrin upregulation therapies will be of potential wide utility in AD. Comparatively little is known about the regulation of filaggrin gene expression, although this is now an area of active interest by academia and pharma alike. The fact that filaggrin expression has been shown to be regulated by environmental humidity (Katagiri et al., 2003Katagiri C. Sato J. Nomura J. et al.Changes in environmental humidity affect the water-holding property of the stratum corneum and its free amino acid content, and the expression of filaggrin in the epidermis of hairless mice.J Dermatol Sci. 2003; 31: 29-35Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar) indicates that there are signaling pathways in the skin that actively control filaggrin expression and skin barrier homeostasis in general. These are tractable problems that will lead to specific therapeutic approaches once these pathways are fully understood and targeted pharmacologically. The authors state no conflict of interest." @default.
• W2240371028 created "2016-06-24" @default.
• W2240371028 creator A5013626670 @default.
• W2240371028 creator A5077872633 @default.
• W2240371028 date "2012-11-01" @default.
• W2240371028 modified "2023-10-13" @default.
• W2240371028 title "Heritable Filaggrin Disorders: The Paradigm of Atopic Dermatitis" @default.
• W2240371028 cites W1916016072 @default.
• W2240371028 cites W1972964808 @default.
• W2240371028 cites W1975512501 @default.
• W2240371028 cites W1977547183 @default.
• W2240371028 cites W1994554109 @default.
• W2240371028 cites W2007177569 @default.
• W2240371028 cites W2045069202 @default.
• W2240371028 cites W2055580813 @default.
• W2240371028 cites W2057098942 @default.
• W2240371028 cites W2058035002 @default.
• W2240371028 cites W2066224059 @default.
• W2240371028 cites W2068176013 @default.
• W2240371028 cites W2072798835 @default.
• W2240371028 cites W2087256989 @default.
• W2240371028 cites W2114978456 @default.
• W2240371028 cites W2115672863 @default.
• W2240371028 cites W2118203548 @default.
• W2240371028 cites W2129016936 @default.
• W2240371028 cites W2133865811 @default.
• W2240371028 cites W2140192959 @default.
• W2240371028 cites W2157168691 @default.
• W2240371028 cites W2159271088 @default.
• W2240371028 cites W2164900506 @default.
• W2240371028 cites W2240371028 @default.
• W2240371028 doi "https://doi.org/10.1038/skinbio.2012.6" @default.
• W2240371028 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26875437" @default.
• W2240371028 hasPublicationYear "2012" @default.
• W2240371028 type Work @default.
• W2240371028 sameAs 2240371028 @default.
• W2240371028 citedByCount "24" @default.
• W2240371028 countsByYear W22403710282012 @default.
• W2240371028 countsByYear W22403710282013 @default.
• W2240371028 countsByYear W22403710282014 @default.
• W2240371028 countsByYear W22403710282015 @default.
• W2240371028 countsByYear W22403710282016 @default.
• W2240371028 countsByYear W22403710282017 @default.
• W2240371028 countsByYear W22403710282018 @default.
• W2240371028 countsByYear W22403710282019 @default.
• W2240371028 countsByYear W22403710282020 @default.
• W2240371028 countsByYear W22403710282022 @default.
• W2240371028 crossrefType "journal-article" @default.
• W2240371028 hasAuthorship W2240371028A5013626670 @default.
• W2240371028 hasAuthorship W2240371028A5077872633 @default.
• W2240371028 hasBestOaLocation W22403710281 @default.
• W2240371028 hasConcept C16005928 @default.
• W2240371028 hasConcept C190684412 @default.
• W2240371028 hasConcept C2778329239 @default.
• W2240371028 hasConcept C71924100 @default.
• W2240371028 hasConceptScore W2240371028C16005928 @default.
• W2240371028 hasConceptScore W2240371028C190684412 @default.
• W2240371028 hasConceptScore W2240371028C2778329239 @default.
• W2240371028 hasConceptScore W2240371028C71924100 @default.
• W2240371028 hasLocation W22403710281 @default.
• W2240371028 hasLocation W22403710282 @default.
• W2240371028 hasLocation W22403710283 @default.
• W2240371028 hasOpenAccess W2240371028 @default.
• W2240371028 hasPrimaryLocation W22403710281 @default.
• W2240371028 hasRelatedWork W2048409844 @default.
• W2240371028 hasRelatedWork W2049314618 @default.
• W2240371028 hasRelatedWork W2066797494 @default.
• W2240371028 hasRelatedWork W2117538393 @default.
• W2240371028 hasRelatedWork W2358243741 @default.
• W2240371028 hasRelatedWork W2959186448 @default.
• W2240371028 hasRelatedWork W4229899331 @default.
• W2240371028 hasRelatedWork W4234841647 @default.
• W2240371028 hasRelatedWork W4308132322 @default.
• W2240371028 hasRelatedWork W1834161415 @default.
• W2240371028 hasVolume "132" @default.
• W2240371028 isParatext "false" @default.
• W2240371028 isRetracted "false" @default.
• W2240371028 magId "2240371028" @default.
• W2240371028 workType "article" @default.