title: Development of an ichthyosiform phenotype in Alox12b-deficient mouse skin transplants.
abstract: 12R-lipoxygenase (12R-LOX) represents a key enzyme of a recently identified eicosanoid pathway in the skin that plays an essential role in the establishment and/or maintenance of the epidermal barrier function. Genetic studies show that loss-of-function mutations in ALOX12B, encoding 12R-LOX, and in ALOXE3, encoding another closely related LOX involved in this pathway, are the second most common cause for autosomal recessive congenital ichthyosis (ARCI). To investigate the pathomechanism of ARCI and the function of 12R-LOX, we recently generated a 12R-LOX knockout model. 12R-LOX-deficient mice die rapidly after birth from severe barrier dysfunction without exhibiting an obvious cutaneous phenotype. Thus, we analyzed the adult phenotype of 12R-LOX(-/-) skin transplanted onto nude mice. 12R-LOX(-/-) skin develops an ichthyosiform appearance with thickening of the epidermis, hyperproliferation, hypergranulosis, focal parakeratosis, and severe hyperkeratosis. The adult mutant mouse skin phenotype closely reproduces the ichthyosis phenotype seen in patients with ALOX12B mutations. Western blot analysis revealed restoration of profilaggrin processing that used to be disturbed in neonatal mutant skin and overexpression of filaggrin, involucrin, and repetin. The results indicate that 12R-LOX knockout mice may represent a useful animal model for a detailed analysis of mechanisms involved in ARCI forms that are associated with impaired LOX metabolism.
authors.affiliation: Genome Modifications and Carcinogenesis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: de Juanes
authors.forename: Nikolas
authors.initials: N
authors.lastname: Epp
authors.forename: Susanne
authors.initials: S
authors.lastname: Latzko
authors.forename: Mareen
authors.initials: M
authors.lastname: Neumann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Stark
authors.forename: Peter
authors.initials: P
authors.lastname: Krieg
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism*; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000648:ultrastructure; D016038:Skin Transplantation
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human