Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march
2016; Elsevier BV; Volume: 138; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2016.06.002
ISSN1097-6825
AutoresGyohei Egawa, Kenji Kabashima,
Tópico(s)Neonatal skin health care
ResumoAtopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic “atopic (allergic) march.” In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function. Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic “atopic (allergic) march.” In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. The skin covers the entire body and protects us from the external environment. When this barrier is impaired, external toxins are able to penetrate the skin and induce inflammation. Over the last decade, numerous studies have demonstrated that skin barrier dysfunction is a critical component of atopic dermatitis (AD).1Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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 (1479) Google Scholar, 2Elias P.M. Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis.Curr Allergy Asthma Rep. 2009; 9: 265-272Crossref PubMed Scopus (31) Google Scholar, 3Cork M.J. Danby S.G. Vasilopoulos Y. Hadgraft J. Lane M.E. Moustafa M. et al.Epidermal barrier dysfunction in atopic dermatitis.J Invest Dermatol. 2009; 129: 1892-1908Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar In particular, inherited defects in epidermal barrier proteins facilitate the interaction of external antigens with skin-resident immune cells, driving local inflammation that can also lead to systemic immune responses. This is the outside-in hypothesis of AD pathogenesis, and it helps to explain the increased risk patients with AD have of having food allergies, asthma, and allergic rhinitis later in life, the progression to which is known as the atopic (allergic) march.4Spergel J.M. Paller A.S. Atopic dermatitis and the atopic march.J Allergy Clin Immunol. 2003; 112: S118-S127Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar In addition, it is now evident that this secondary immunologic activation results in further attenuation of the skin barrier, which further exacerbates inflammation and allergic sensitization to environmental allergens.5Elias P.M. Steinhoff M. “Outside-to-inside”(and now back to “outside”) pathogenic mechanisms in atopic dermatitis.J Invest Dermatol. 2008; 128: 1067-1070Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These observations suggest that maintaining skin barrier function is important for both the effective management of AD and prevention of the development of subsequent allergic diseases. In this article we summarize how the physical skin barrier is organized and review its link to AD pathogenesis. This article does not cover chemical and biological skin barriers (eg, the skin acid mantle, antimicrobial peptides, and bacterial flora) or immune cell–mediated skin barrier function. Reviews covering these aspects can be found elsewhere.6Kuo I.-H. Yoshida T. De Benedetto A. Beck L.A. The cutaneous innate immune response in patients with atopic dermatitis.J Allergy Clin Immunol. 2013; 131: 266-278Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 7Kubo A. Nagao K. Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases.J Clin Invest. 2012; 122: 440-447Crossref PubMed Scopus (114) Google Scholar, 8Nakamizo S. Egawa G. Honda T. Nakajima S. Belkaid Y. Kabashima K. Commensal bacteria and cutaneous immunity.Semin Immunopathol. 2015; 37: 73-80Crossref PubMed Scopus (12) Google Scholar The barrier function of the skin is largely dependent on the stratum corneum (SC), the outermost layer of the epidermis (Fig 1, A and B). The SC is formed during the course of a tightly regulated processes of keratinocyte differentiation called cornification.9Matsui T. Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum.Int Immunol. 2015; 27: 269-280Crossref PubMed Scopus (19) Google Scholar Cornification is achieved by keratinocytes passing through 4 cell layers of the epidermis: the stratum basale, the stratum spinosum, the stratum granulosum (SG), and the SC (Fig 1, B). In the SG keratinocytes start to produce 2 membrane-circumscribed granules: keratohyalin granules and lamellar bodies. Keratohyalin granules contain intracellular components of the SC (eg, filaggrin [FLG], loricrin, and keratin filaments), whereas lamellar bodies contain extracellular components (eg, lipids, corneodesmosin, and kallikreins [KLKs]). In the SC keratinocytes become flattened and denucleated (which are then called corneocytes), whereas their membranes are replaced by a specific barrier structure known as the cornified envelope (CE; Fig 1, C and D). At the transition from the SG to the SC, lamellar bodies are secreted into the intercellular space between the corneocytes and fill with lipids. These structures are often described as bricks (corneocytes) and mortar (intercellular lipids), which together provide a highly hydrophobic barrier against the environment. Below, we describe the formation of the SC barrier in terms of the following 5 categories and review their link to AD pathogenesis: (1) FLG metabolism; (2) the CE; (3) intercellular lipids; (4) the corneodesmosome; and (5) corneocyte desquamation. The genes involved in each process are listed in Table I.1Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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 (1479) Google Scholar, 10Leyvraz C. Charles R.-P. Rubera I. Guitard M. Rotman S. Breiden B. et al.The epidermal barrier function is dependent on the serine protease CAP1/Prss8.J Cell Biol. 2005; 170: 487-496Crossref PubMed Scopus (169) Google Scholar, 11Matsui T. Miyamoto K. Kubo A. Kawasaki H. Ebihara T. Hata K. et al.SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.EMBO Mol Med. 2011; 3: 320-333Crossref PubMed Scopus (36) Google Scholar, 12Nachat R. Méchin M.-C. Takahara H. Chavanas S. Charveron M. Serre G. et al.Peptidylarginine deiminase isoforms 1–3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin.J Invest Dermatol. 2005; 124: 384-393Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Hoste E. Kemperman P. Devos M. Denecker G. Kezic S. Yau N. et al.Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.J Invest Dermatol. 2011; 131: 2233-2241Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 14Kamata Y. Taniguchi A. Yamamoto M. Nomura J. Ishihara K. Takahara H. et al.Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids.J Biol Chem. 2009; 284: 12829-12836Crossref PubMed Scopus (0) Google Scholar, 15Kawasaki H. Nagao K. Kubo A. Hata T. Shimizu A. Mizuno H. et al.Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.J Allergy Clin Immunol. 2012; 129: 1538-1546.e6Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 16Saunders S.P. Moran T. Floudas A. Wurlod F. Kaszlikowska A. Salimi M. et al.Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.J Allergy Clin Immunol. 2016; 13: 482-491Abstract Full Text Full Text PDF Scopus (13) Google Scholar, 17Smith 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 (589) Google Scholar, 18Margolis D.J. Gupta J. Apter A.J. Ganguly T. Hoffstad O. Papadopoulos M. et al.Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.J Allergy Clin Immunol. 2014; 133: 784-789Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 19Djian P. Easley K. Green H. Targeted ablation of the murine involucrin gene.J Cell Biol. 2000; 151: 381-388Crossref PubMed Scopus (58) Google Scholar, 20Määttä A. DiColandrea T. Groot K. Watt F.M. Gene targeting of envoplakin, a cytoskeletal linker protein and precursor of the epidermal cornified envelope.Mol Cell Biol. 2001; 21: 7047-7053Crossref PubMed Scopus (0) Google Scholar, 21Aho S. Li K. Ryoo Y. McGee C. Ishida-Yamamoto A. Uitto J. et al.Periplakin gene targeting reveals a constituent of the cornified cell envelope dispensable for normal mouse development.Mol Cell Biol. 2004; 24: 6410-6418Crossref PubMed Scopus (0) Google Scholar, 22Koch P.J. De Viragh P.A. Scharer E. Bundman D. Longley M.A. Bickenbach J. et al.Lessons from loricrin-deficient mice compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein.J Cell Biol. 2000; 151: 389-400Crossref PubMed Scopus (0) Google Scholar, 23Laiho E. Ignatius J. Mikkola H. Yee V.C. Teller D.C. Niemi K.-M. et al.Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.Am J Hum Genet. 1997; 61: 529-538Abstract Full Text PDF PubMed Google Scholar, 24Cassidy A.J. van Steensel M.A. Steijlen P.M. van Geel M. van der Velden J. Morley S.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 25Eckl K.-M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 26Kelsell P.D. Norgett E.E. Unsworth H. Teh M.-T. Cullup T. Mein C.A. et al.Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.Am J Hum Genet. 2005; 76: 794-803Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 27Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120.e4Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 28Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 29Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; 45: 1244-1248Crossref PubMed Scopus (79) Google Scholar, 30Walley A.J. Chavanas S. Moffatt M.F. Esnouf R.M. Ubhi B. Lawrence R. et al.Gene polymorphism in Netherton and common atopic disease.Nat Genet. 2001; 29: 175-178Crossref PubMed Scopus (287) Google Scholar, 31Kato A. Fukai K. Oiso N. Hosomi N. Murakami T. Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population.Br J Dermatol. 2003; 148: 665-669Crossref PubMed Scopus (123) Google Scholar, 32Zhao L. Di Z. Zhang L. Wang L. Ma L. Lv Y. et al.Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China.J Eur Acad Dermatol Venereol. 2012; 26: 572-577Crossref PubMed Scopus (0) Google Scholar, 33Lee J.H. Kim K.W. Gee H.Y. Lee J. Lee K.-H. Park H.-S. et al.A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children.J Allergy Clin Immunol. 2011; 128: 1326-1334.e3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Leclerc E.A. Huchenq A. Mattiuzzo N.R. Metzger D. Chambon P. Ghyselinck N.B. et al.Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.J Cell Sci. 2009; 122: 2699-2709Crossref PubMed Scopus (0) Google Scholar, 35Carregaro F. Stefanini A.C.B. Henrique T. Tajara E.H. Study of small proline-rich proteins (SPRRs) in health and disease: a review of the literature.Arch Dermatol Res. 2013; 305: 857-866Crossref PubMed Scopus (0) Google Scholar, 36Matsuki M. Yamashita F. Ishida-Yamamoto A. Yamada K. Kinoshita C. Fushiki S. et al.Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase).Proc Natl Acad Sci U S A. 1998; 95: 1044-1049Crossref PubMed Scopus (0) Google Scholar, 37Bognar P. Nemeth I. Mayer B. Haluszka D. Wikonkal N. Ostorhazi E. et al.Reduced inflammatory threshold indicates skin barrier defect in transglutaminase 3 knockout mice.J Invest Dermatol. 2014; 134: 105-111Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 38de Juanes S. Epp N. Latzko S. Neumann M. Fürstenberger G. Hausser I. et al.Development of an ichthyosiform phenotype in Alox12b-deficient mouse skin transplants.J Invest Dermatol. 2009; 129: 1429-1436Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 39Krieg P. Rosenberger S. de Juanes S. Latzko S. Hou J. Dick A. et al.Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation.J Invest Dermatol. 2013; 133: 172-180Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 40Yanagi T. Akiyama M. Nishihara H. Ishikawa J. Sakai K. Miyamura Y. et al.Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.Am J Pathol. 2010; 177: 106-118Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 41Chidgey M. Brakebusch C. Gustafsson E. Cruchley A. Hail C. Kirk S. et al.Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.J Cell Biol. 2001; 155: 821-832Crossref PubMed Scopus (125) Google Scholar, 42Ruiz P. Birchmeier W. The plakoglobin knock-out mouse: a paradigm for the molecular analysis of cardiac cell junction formation.Trends Cardiovasc Med. 1998; 8: 97-101Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Sklyarova T. Bonné S. D'hooge P. Denecker G. Goossens S. De Rycke R. et al.Plakophilin-3-deficient mice develop hair coat abnormalities and are prone to cutaneous inflammation.J Invest Dermatol. 2008; 128: 1375-1385Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 44Furio L. de Veer S. Jaillet M. Briot A. Robin A. Deraison C. et al.Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome.J Exp Med. 2014; 211: 499-513Crossref PubMed Scopus (30) Google Scholar, 45Hansson L. Bäckman A. Ny A. Edlund M. Ekholm E. Hammarström B.E. et al.Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis.J Invest Dermatol. 2002; 118: 444-449Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 46Stefansson K. Brattsand M. Ny A. Glas B. Egelrud T. Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum.Biol Chem. 2006; 387: 761-768Crossref PubMed Scopus (51) Google Scholar, 47Yang T. Liang D. Koch P.J. Hohl D. Kheradmand F. Overbeek P.A. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/-mice.Genes Dev. 2004; 18: 2354-2358Crossref PubMed Scopus (0) Google ScholarTable IA list of genes involved in the SC formation processGeneGene symbolFunctionAssociated human diseaseKnockout mice phenotypeReferenceFLG metabolism Filaggrin∗Genes with mutations that have been linked to AD pathogenesis.FLGKeratin filament aggregationIchthyosis vulgaris (AD)Skin barrier deficiencySpontaneous dermatitis1Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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 (1479) Google Scholar, 15Kawasaki H. Nagao K. Kubo A. Hata T. Shimizu A. Mizuno H. et al.Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.J Allergy Clin Immunol. 2012; 129: 1538-1546.e6Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 16Saunders S.P. Moran T. Floudas A. Wurlod F. Kaszlikowska A. Salimi M. et al.Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.J Allergy Clin Immunol. 2016; 13: 482-491Abstract Full Text Full Text PDF Scopus (13) Google Scholar, 17Smith 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 (589) Google Scholar Filaggrin 2∗Genes with mutations that have been linked to AD pathogenesis.FLG2Similar to FLG?18Margolis D.J. Gupta J. Apter A.J. Ganguly T. Hoffstad O. Papadopoulos M. et al.Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.J Allergy Clin Immunol. 2014; 133: 784-789Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Cap1/Prss8PRSS8Cleave pro-FLG to FLGSkin barrier deficiency10Leyvraz C. Charles R.-P. Rubera I. Guitard M. Rotman S. Breiden B. et al.The epidermal barrier function is dependent on the serine protease CAP1/Prss8.J Cell Biol. 2005; 170: 487-496Crossref PubMed Scopus (169) Google Scholar SASpase∗Genes with mutations that have been linked to AD pathogenesis.ASPRV1Cleave pro-FLG to FLGSC dehydration11Matsui T. Miyamoto K. Kubo A. Kawasaki H. Ebihara T. Hata K. et al.SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.EMBO Mol Med. 2011; 3: 320-333Crossref PubMed Scopus (36) Google Scholar Peptidylarginine deiminasePADICitrullination of FLG12Nachat R. Méchin M.-C. Takahara H. Chavanas S. Charveron M. Serre G. et al.Peptidylarginine deiminase isoforms 1–3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin.J Invest Dermatol. 2005; 124: 384-393Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Caspase 14CASP14FLG metabolismSkin barrier deficiency13Hoste E. Kemperman P. Devos M. Denecker G. Kezic S. Yau N. et al.Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.J Invest Dermatol. 2011; 131: 2233-2241Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Calpain 1CAPN1FLG metabolism14Kamata Y. Taniguchi A. Yamamoto M. Nomura J. Ishihara K. Takahara H. et al.Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids.J Biol Chem. 2009; 284: 12829-12836Crossref PubMed Scopus (0) Google Scholar Bleomycin hydrolaseBLMHFLG metabolismPenetrant ring-tail dermatitis14Kamata Y. Taniguchi A. Yamamoto M. Nomura J. Ishihara K. Takahara H. et al.Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids.J Biol Chem. 2009; 284: 12829-12836Crossref PubMed Scopus (0) Google ScholarFormation of CE InvolucrinIVLScaffold of CENo skin phenotype19Djian P. Easley K. Green H. Targeted ablation of the murine involucrin gene.J Cell Biol. 2000; 151: 381-388Crossref PubMed Scopus (58) Google Scholar EnvoplakinEVPLPlakin familyNo skin phenotype20Määttä A. DiColandrea T. Groot K. Watt F.M. Gene targeting of envoplakin, a cytoskeletal linker protein and precursor of the epidermal cornified envelope.Mol Cell Biol. 2001; 21: 7047-7053Crossref PubMed Scopus (0) Google Scholar PeriplakinPPLPlakin familyNo skin phenotype21Aho S. Li K. Ryoo Y. McGee C. Ishida-Yamamoto A. Uitto J. et al.Periplakin gene targeting reveals a constituent of the cornified cell envelope dispensable for normal mouse development.Mol Cell Biol. 2004; 24: 6410-6418Crossref PubMed Scopus (0) Google Scholar LoricrinLORReinforce CEShiny skin22Koch P.J. De Viragh P.A. Scharer E. Bundman D. Longley M.A. Bickenbach J. et al.Lessons from loricrin-deficient mice compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein.J Cell Biol. 2000; 151: 389-400Crossref PubMed Scopus (0) Google Scholar Small proline-rich proteinSPRRReinforce CE35Carregaro F. Stefanini A.C.B. Henrique T. Tajara E.H. Study of small proline-rich proteins (SPRRs) in health and disease: a review of the literature.Arch Dermatol Res. 2013; 305: 857-866Crossref PubMed Scopus (0) Google Scholar Transglutaminase 1TGM1Cross-link CE proteinsARCI-1 (AR)Skin barrier deficiency23Laiho E. Ignatius J. Mikkola H. Yee V.C. Teller D.C. Niemi K.-M. et al.Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.Am J Hum Genet. 1997; 61: 529-538Abstract Full Text PDF PubMed Google Scholar, 36Matsuki M. Yamashita F. Ishida-Yamamoto A. Yamada K. Kinoshita C. Fushiki S. et al.Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase).Proc Natl Acad Sci U S A. 1998; 95: 1044-1049Crossref PubMed Scopus (0) Google Scholar Transglutaminase 3TGM3Cross-link CE proteinsSkin barrier deficiency37Bognar P. Nemeth I. Mayer B. Haluszka D. Wikonkal N. Ostorhazi E. et al.Reduced inflammatory threshold indicates skin barrier defect in transglutaminase 3 knockout mice.J Invest Dermatol. 2014; 134: 105-111Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Transglutaminase 5TGM5Cross-link CE proteinsPeeling skin syndrome 2 (AR)24Cassidy A.J. van Steensel M.A. Steijlen P.M. van Geel M. van der Velden J. Morley S.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarIntercellular lipid lamellae formation 12R-lipoxygenaseALOX12BCeramide processingARCI-2 (AR)Skin barrier deficiencyNeonatal death25Eckl K.-M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 38de Juanes S. Epp N. Latzko S. Neumann M. Fürstenberger G. Hausser I. et al.Development of an ichthyosiform phenotype in Alox12b-deficient mouse skin transplants.J Invest Dermatol. 2009; 129: 1429-1436Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Epidermal lipoxygenase 3ALOX3ECeramide processingARCI-3 (AR)Skin barrier deficiencyNeonatal death25Eckl K.-M. de Juanes S. Kurtenbach J. Nätebus M. Lugassy J. Oji V. et al.Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.J Invest Dermatol. 2009; 129: 1421-1428Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 39Krieg P. Rosenberger S. de Juanes S. Latzko S. Hou J. Dick A. et al.Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation.J Invest Dermatol. 2013; 133: 172-180Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ATP-binding cassette subfamily A member 12ABCA12Transport of lamellar bodyARCI -4A/-4B (AR)[Harlequin ichthyosis]Skin barrier deficiency26Kelsell P.D. Norgett E.E. Unsworth H. Teh M.-T. Cullup T. Mein C.A. et al.Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.Am J Hum Genet. 2005; 76: 794-803Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 40Yanagi T. Akiyama M. Nishihara H. Ishikawa J. Sakai K. Miyamura Y. et al.Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.Am J Pathol. 2010; 177: 106-118Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Tmem79/mattrin∗Genes with mutations that have been linked to AD pathogenesis.TMEM79Secretion of lamellar bodiesSpontaneous dermatitis27Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120.e4Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 28Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarCorneodesmosome Desmoglein1DSG1Cadherin familySAM syndrome†Diseases that might represent AD-like dermatitis. (AR)29Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; 45: 1244-1248Crossref PubMed Scopus (79) Google Scholar Desmocollin 1DCN1Cadherin familySkin barrier deficiency41Chidgey M. Brakebusch C. Gustafsson E. Cruchley A. Hail C. Kirk S. et al.Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.J Cell Biol. 2001; 155: 821-832Crossref PubMed Scopus (125) Google Scholar PlakoglobinJUPArmadillo familyNaxos disease (AR)Embryonic lethal42Ruiz P. Birchmeier W. The plakoglobin knock-out mouse: a paradigm for the molecular analysis of cardiac cell junction formation.Trends Cardiovasc Med. 1998; 8: 97-101Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar PlakophilinPKPArmadillo familySkin fragility syndrome (AR)PKP3-deficient mice have dermatitis43Sklyarova T. Bonné S. D'hooge P. Denecker G. Goossens S. De Rycke R. et al.Plakophilin-3-deficient mice develop hair coat abnormalities and are prone to cutaneous inflammation.J Invest Dermatol. 2008; 128: 1375-1385Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar (Envoplakin)EVPLPlakin familyNo skin phenotype20Määttä A. DiColandrea T. Groot K. Watt F.M. Gene targeting of envoplakin, a cytoskeletal linker protein and precursor of the epidermal cornified envelope.Mol Cell Biol. 2001; 21: 7047-7053Crossref PubMed Scopus (0) Google Scholar (Periplakin)PPLPlakin familyNo skin phenotype21Aho S. Li K. Ryoo Y. McGee C. Ishida-Yamamoto A. Uitto J. et al.Periplakin gene targeting reveals a constituent of the cornified cell envelope dispensable for normal mouse development.Mol Cell Biol. 2004; 24: 6410-6418Crossref PubMed Scopus (0) Google Scholar CorneodesmosinCDSNSupport corneodesmosome adhesionPeeling skin syndrome 1†Diseases that might represent AD-like dermatitis. (AR)Skin barrier deficiencyNeonatal death34Leclerc E.A. Huchenq A. Mattiuzzo N.R. Metzger D. Chambon P. Ghyselinck N.B. et al.Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.J Cell Sci. 2009; 122: 2699-2709Crossref PubMed Scopus (0) Google ScholarCorneocyte desquamation Kallikrein5KLK5Serine proteaseSkin inflammation (when overexpressed)44Furio L. de Veer S. Jaillet M. Briot A. Robin A. Deraison C. et al.Transgenic kallikrein 5 mice reproduce major cutaneous and syste
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