title: Peroxidasin is essential for eye development in the mouse.
abstract: Mutations in Peroxidasin (PXDN) cause severe inherited eye disorders in humans, such as congenital cataract, corneal opacity and developmental glaucoma. The role of peroxidasin during eye development is poorly understood. Here, we describe the first Pxdn mouse mutant which was induced by ENU (N-ethyl-N-nitrosourea) and led to a recessive phenotype. Sequence analysis of cDNA revealed a T3816A mutation resulting in a premature stop codon (Cys1272X) in the peroxidase domain. This mutation causes severe anterior segment dysgenesis and microphthalmia resembling the manifestations in patients with PXDN mutations. The proliferation and differentiation of the lens is disrupted in association with aberrant expression of transcription factor genes (Pax6 and Foxe3) in mutant eyes. Additionally, Pxdn is involved in the consolidation of the basement membrane and lens epithelium adhesion in the ocular lens. Lens material including γ-crystallin is extruded into the anterior and posterior chamber due to local loss of structural integrity of the lens capsule as a secondary damage to the anterior segment development leading to congenital ocular inflammation. Moreover, Pxdn mutants exhibited an early-onset glaucoma and progressive retinal dysgenesis. Transcriptome profiling revealed that peroxidasin affects the transcription of developmental and eye disease-related genes at early eye development. These findings suggest that peroxidasin is necessary for cell proliferation and differentiation and for basement membrane consolidation during eye development. Our studies provide pathogenic mechanisms of PXDN mutation-induced congenital eye diseases.
authors.affiliation: Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yan
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sabrautzki
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany, German Center for Diabetes Research (DZD), Neuherberg, Germany and Chair of Experimental Genetics, Technische Universität München, Center of Life and Food Sciences, Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Institute of Experimental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany, German Center for Diabetes Research (DZD), Neuherberg, Germany and Chair of Experimental Genetics, Technische Universität München, Center of Life and Food Sciences, Freising-Weihenstephan, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany, German Mouse Clinic, Neuherberg, Germany, graw@helmholtz-muenchen.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005123:Eye / Q000196:embryology* / Q000378:metabolism*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005838:Genotype; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D009898:Optic Disk / Q000196:embryology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D009195:Peroxidase / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D000097423:Peroxidasin
chemical_list: D016326:Extracellular Matrix Proteins; D009195:Peroxidase; D000097423:Peroxidasin