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.
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Acknowledgements
We are grateful to the families for their participation. This work was supported by grant R21EY022779-01 to Dr Anne Slavotinek from the National Eye Institute, National Institutes of Health. We thank the California Department of Public Health Maternal Child and Adolescent Health Division for providing data for some analyses. The findings and conclusions in this report are those of the authors and do not necessarily represent the view of the California Department of Public Health.
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Choi, A., Lao, R., Ling-Fung Tang, P. et al. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet 23, 337–341 (2015). https://doi.org/10.1038/ejhg.2014.119
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DOI: https://doi.org/10.1038/ejhg.2014.119
