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Xiaoqiang Xiao, Chukai Huang, Yingjie Cao, Shaowan Chen, Yanxuan Xu, Haoyu Chen, Chipui Pang, Mingzhi Zhang; Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(13):4277-4284. doi: https://doi.org/10.1167/iovs.19-27545.
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Juvenile-onset open-angle glaucoma (JOAG), if left untreated, will lead to severe visual disability. The purpose of this study was to identify the disease-causing mutations in a Chinese JOAG family.
We recruited a Chinese JOAG family and unrelated primary open-angle glaucoma (POAG) patients (270, Chinese), and performed whole-exome sequencing (WES) to screen the sequence variations. Variants identified by WES were validated by Sanger sequencing. Subsequently, qPCR and Western blotting were used to determine the expression of wild-type (WT) and its mutated-type (MT) of 2′-5′-oligoadenylate synthetase 3 (OAS3) genes.
Seventeen heterozygous candidate variants were revealed in the JOAG family based on the screening of WES data. Of those, the heterozygous variant exon11:c.2299C>T: p.Arg767Cys in OAS3, a gene used to synthesize 2′-5′-oligoadenylate (2–5A), co-segregates with the disease phenotype. One unrelated POAG patient also carried this variant, but this variant was absent in 200 nonglaucoma healthy controls. Analysis of the Arg767Cys mutation with PolyPhen2, CADD, and SIFT all suggest that it is pathogenic. This arginine residue is highly conserved in all selected OAS3 orthologs. On the other hand, in peripheral blood samples, the mRNA expression of OAS3 in patients significantly decreased compared with unaffected controls. Moreover, the expression level of recombinant OAS3 protein (mutated Arg767Cys) also observably reduced compared with level of WT protein in HEK293T cells.
Our study revealed a heterozygous mutation in OAS3 from a Chinese JOAG family. And this mutation showed a deleterious effect to the expression of OAS3.
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