Homozygous Mutations in PXDN Cause Congenital Cataract, Corneal Opacity, and Developmental Glaucoma

Abstract

Anterior segment dysgenesis describes a group of heterogeneous developmental disorders that affect the anterior chamber of the eye and are associated with an increased risk of glaucoma. Here, we report homozygous mutations in peroxidasin (PXDN) in two consanguineous Pakistani families with congenital cataract-microcornea with mild to moderate corneal opacity and in a consanguineous Cambodian family with developmental glaucoma and severe corneal opacification. These results highlight the diverse ocular phenotypes caused by PXDN mutations, which are likely due to differences in genetic background and environmental factors. Peroxidasin is an extracellular matrix-associated protein with peroxidase catalytic activity, and we confirmed localization of the protein to the cornea and lens epithelial layers. Our findings imply that peroxidasin is essential for normal development of the anterior chamber of the eye, where it may have a structural role in supporting cornea and lens architecture as well as an enzymatic role as an antioxidant enzyme in protecting the lens, trabecular meshwork, and cornea against oxidative damage.

Multidomain Human Peroxidasin 1 Is a Highly Glycosylated and Stable Homotrimeric High Spin Ferric Peroxidase

“…been shown that the absence of the enzyme has severe and fatal impacts in model organisms (5,6,15), but detrimental mutations in humans have also been reported (35,36). Therefore, a better understanding of the biochemical function and biophysical properties can be of crucial importance.…”

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

“…Of the four mutations that we identified, three were novel, whereas p.(Arg341*) has been previousIy published. 26 In the other individuals with A/M selected because of additional anterior segment abnormalities, we did not find two pathogenic sequence alterations in any patient. Mutations have been submitted to the Leiden Open Variation Database (http:// databases.lovd.nl/shared/genes/PXDN).…”

“…A fourth family with PXDN loss of function had developmental glaucoma, buphthalmos and extensive corneal opacification. 26 No patient had neurological abnormalities as seen in our first family. In all reported families, unaffected carriers have had no ocular abnormalities.…”

“…26 Defining phenotypic features for these families were microcornea and corneal opacification, with varying degrees of intrafamilial expression, but not microphthalmia. A fourth family with PXDN loss of function had developmental glaucoma, buphthalmos and extensive corneal opacification.…”

“…From the four genes, only PXDN was known to be involved in developmental eye defects. 26 The predicted mutations in PXDN (mRNA reference sequence NM_012293.1, Chromosome reference number NC_000002.11, National Center for Biotechnology Information Gene, http://www. ncbi.nlm.nih.gov/gene; Ensembl genomic reference ENSG00000 130508 and transcript ENST00000252804; http://www.ensembl.org/ index.html) in the first family were verified by Sanger sequencing: a maternally inherited, nonsense mutation: c.1021C4T, predicting p.(Arg341*) and a paternally inherited, intragenic deletion resulting in a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67) (Figures 2a,b and Figure 3a).…”