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Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss\u2010of\u2010function mutations of these genes constitute a risk factor for atopic dermatitis and eczema\u2010related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for <jats:italic>Flg<\/jats:italic> and <jats:italic>Hrnr<\/jats:italic> provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>By using appropriate targeting vectors and breeding strategies, we established a homozygous <jats:italic>FlgHrnr<\/jats:italic> double\u2010deficient (<jats:italic>FlgHrnr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mouse model lacking both genes including the intergenomic sequence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, <jats:italic>FlgHrnr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, <jats:italic>FlgHrnr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the <jats:italic>stratum corneum<\/jats:italic>. Surprisingly, although the immune system revealed no aberrations under steady\u2010state conditions, <jats:italic>FlgHrnr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Together, our<jats:italic> FlgHrnr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.13756","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T08:24:27Z","timestamp":1551687867000},"page":"1327-1339","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin\u2010hornerin (<i>FlgHrnr<\/i><sup>\u2212\/\u2212<\/sup>) double\u2010deficient mice"],"prefix":"10.1111","volume":"74","author":[{"given":"Sebastian","family":"Rahrig","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith M.","family":"Dettmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birka","family":"Brauns","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology University Medical Center Rostock Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena N.","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3139-129X","authenticated-orcid":false,"given":"Timo","family":"Buhl","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanja","family":"Kezic","sequence":"additional","affiliation":[{"name":"Academic Medical Center Coronel Institute of Occupational Health Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter M.","family":"Elias","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of California San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Weidinger","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy University Hospital Schleswig\u2010Holstein Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Mempel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"},{"name":"Lower Saxony Institute of Occupational Dermatology University Medical Center G\u00f6ttingen and University of Osnabr\u00fcck G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P.","family":"Sch\u00f6n","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University G\u00f6ttingen Germany"},{"name":"Lower Saxony Institute 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