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A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene.

ABSTRACT: PURPOSE: To undertake mutation screening in the connexin 46 (GJA3) gene in seven congenital cataract families of Indian origin. METHODS: Seven Indian families with congenital cataract were analyzed by detailed family history and clinical evaluation. Each family had two to five affected members. Mutation screening was carried out in the candidate gene, connexin 46 (GJA3), using bidirectional sequencing of amplified products. Segregation of the observed change with the disease phenotype was further tested by restriction fragment length polymorphism (RFLP). RESULTS: Sequencing of the coding region of GJA3 showed the presence of a novel, heterozygous C260T change in one family (CC-472) who had two affected members. The cataract phenotype gave the appearance like a "pearl box" in these two affected individuals of this family. The observed C260T substitution created a novel restriction enzyme site for NlaIII and resulted in substitution of highly conserved threonine at position 87 by methionine (T87M). NlaIII restriction digestion analysis revealed this nucleotide change was not in unaffected members of this family or in 100 unrelated control subjects (200 chromosomes) with the same ethnic background. CONCLUSIONS: This is a novel mutation identified in the second transmembrane domain of the connexin 46. These findings thus expand the mutation spectrum of the GJA3 in association with congenital cataract.

SUBMITTER: Guleria K

PROVIDER: S-EPMC2768755 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene.

Guleria Kamlesh K Vanita Vanita V Singh Daljit D Singh Jai Rup JR

Molecular vision 20070604

<h4>Purpose</h4>To undertake mutation screening in the connexin 46 (GJA3) gene in seven congenital cataract families of Indian origin.<h4>Methods</h4>Seven Indian families with congenital cataract were analyzed by detailed family history and clinical evaluation. Each family had two to five affected members. Mutation screening was carried out in the candidate gene, connexin 46 (GJA3), using bidirectional sequencing of amplified products. Segregation of the observed change with the disease phenoty ...[more]

PMID: 17615540

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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

A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene.

Publications

A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene.

Similar Datasets

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