title: Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis.
abstract: We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Choi
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lao
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ling-Fung Tang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Eunice
authors.initials: E
authors.lastname: Wan
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA.
authors.forename: Wasima
authors.initials: W
authors.lastname: Mayer
authors.affiliation: Division of Medical Genetics, Einstein Medical Center, Philadelphia, PA, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Bardakjian
authors.affiliation: Division of Neonatology and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Division of Medical Genetics, Einstein Medical Center, Philadelphia, PA, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
mesh_terms: D019943:Amino Acid Substitution; D000951:Antigens, Neoplasm / Q000235:genetics*; D002675:Child, Preschool; D059472:Exome; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010544:Peroxidases; D010641:Phenotype; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D000097423:Peroxidasin
chemical_list: D000951:Antigens, Neoplasm; D010544:Peroxidases; D017472:Receptors, Interleukin-1; C535215:PXDN protein, human; D000097423:Peroxidasin