Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

Abstract

Citation: Xiao X, Huang C, Cao Y, et al. Exome sequencing reveals a heterozygous OAS3 mutation in a Chinese family with juvenile-onset open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60:4277-4284. https://doi.org/ 10.1167/iovs.19-27545 PURPOSE.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. METHODS.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 0 -5 0 -oligoadenylate synthetase 3 (OAS3) genes. RESULTS.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 0 -5 0 -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. CONCLUSIONS.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.

Juvenile open angle glaucoma: current diagnosis and management

“…The patient had marked optic atrophy, a normal anterior segment, and dysmorphic facial features that may be associated with Axenfeld-Rieger syndrome. Xiao et al [13] conducted a study on a Chinese JOAG family and found a heterozygous pathogenic OAS3 variant that segregates with disease phenotype. Yang et al [14 ▪ ] conducted an additional case report in a Chinese family with JOAG and found heterozygous variants in OLFM2 and SIX6 genes which are thought to be pathogenic when coinherited.…”

Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse

“…Currently, many disease-causing variants were distributed to several genes, including MYOC, OPTN, CYP1B1, NTF4, OAS3, SPATA13/ASEF2, TBK1, and WDR36 in glaucoma. [4][5][6][7] Also, the genome-wide association studies (GWAS) revealed 127 POAG risk loci, such as CAV1/CAV2, TMCO1, SIX6, CDKN2B-AS1, FNDC3B, ANKRD55-MAP3K1, FMNL2, LMX1B, LHPP, HMGA2, NR1H3, PDE7BTMTC2, IKZF2, MEIS2, CADM2, DGKG, ANKH, RAMP, MADD, SEPT9, EXOC2, LOXL1, ABCA1, ARHGEF12, AFAP1, ANGPTL7, SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, SMAD6, and GMDS. [4][5][6][7][8][9][10][11] However, more than 90% of POAG cases remain genetically unexplained based on current diseasecausing genes.…”

“…[4][5][6][7] Also, the genome-wide association studies (GWAS) revealed 127 POAG risk loci, such as CAV1/CAV2, TMCO1, SIX6, CDKN2B-AS1, FNDC3B, ANKRD55-MAP3K1, FMNL2, LMX1B, LHPP, HMGA2, NR1H3, PDE7BTMTC2, IKZF2, MEIS2, CADM2, DGKG, ANKH, RAMP, MADD, SEPT9, EXOC2, LOXL1, ABCA1, ARHGEF12, AFAP1, ANGPTL7, SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, SMAD6, and GMDS. [4][5][6][7][8][9][10][11] However, more than 90% of POAG cases remain genetically unexplained based on current diseasecausing genes. 10,12 Therefore, identifying more diseasecausing mutations is important for early diagnosis and treatment of glaucoma.…”

“…Through linkage analyses, more and more genetic elements which contribute to the pathogenesis of POAG were discovered. Currently, many disease‐causing variants were distributed to several genes, including MYOC , OPTN , CYP1B1 , NTF4 , OAS3, SPATA13/ASEF2, TBK1 , and WDR36 in glaucoma 4–7 . Also, the genome‐wide association studies (GWAS) revealed 127 POAG risk loci, such as CAV1/CAV2, TMCO1, SIX6, CDKN2B‐AS1, FNDC3B, ANKRD55‐MAP3K1, FMNL2, LMX1B, LHPP, HMGA2, NR1H3, PDE7BTMTC2, IKZF2, MEIS2, CADM2, DGKG, ANKH, RAMP, MADD, SEPT9, EXOC2, LOXL1, ABCA1, ARHGEF12, AFAP1 , ANGPTL7 , SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, SMAD6, and GMDS 4–11 .…”