Dataset Information

Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.

ABSTRACT: Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC.

SUBMITTER: Yao Y

PROVIDER: S-EPMC5587237 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.

Yao Yihua Y Zheng Xuedong X Ge Xianglian X Xiu Yanghui Y Zhang Liu L Fang Weifang W Zhao Junzhao J Gu Feng F Zhu Yihua Y

PloS one 20170906 9

Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T ...[more]

PMID: 28877251

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Project description:PurposeTo identify a novel disease-causing mutation of the GJA3 (gap junction alpha-3 protein) gene in a Chinese family with autosomal dominant congenital cataract (ADCC).MethodsOne family was examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Genetic linkage analysis was performed on the known genetic loci for ADCC with a panel of polymorphic markers, and then mutations were screened by direct sequencing. Whenever substitutions were identified in a patient, high-resolution melt curve analysis (HRM) was performed on all available family members and 100 normal controls. Bioinformatics analysis was undergone by the Garnier-Osguthorpe-Robson (GOR) and the PolyPhen (polymorphism phenotyping) programs to predict the effect of variants detected on secondary structure and protein function of the GJA3 protein.ResultsClinical examination and pedigree analysis revealed one four-generation family with congenital nuclear coralliform cataracts. Significant two-point LOD (linkage odd disequilibrium) score was generated at marker D13S292 (Z(max)=2.51, θ=0), and further linkage and haplotype studies confined the disease locus to 13q11-13. Mutations screening of GJA3 in this family revealed an A→T transversion at position 563 (p.N188I) of the cDNA sequence. This novel missense mutation co-segregated with the affected members of the pedigree, but is not present in the unaffected relatives or 100 normal individuals. Secondary structure prediction suggested that the mutant GJA8 188I would replace three turns "T" with three β sheet "E" at amino acid 189-191 and a β sheet "E" with a turn "T" at position 194.ConclusionsNovel missense mutation in the second extracellular loop (E2) was detected, causing coral-like opacities involving embryonic and fetal nucleus surrounded by blue punctate opacities in the cortical zone of the lens. The results further suggested that the extracellular loop was the mutation hotspot of GJA3.

Dataset Information

Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.

Publications

Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.

Similar Datasets

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