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.