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Debbie S Kuo, Jared Sokol, Anne M Slavotinek, Douglas B Gould; Novel GJA8 mutation in transmembrane domain IV associated with hereditary cataract. Invest. Ophthalmol. Vis. Sci. 2016;57(12):652.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital cataracts can be isolated in about 70% of cases or associated with other abnormalities such as anterior segment dysgenesis and microphthalmia. Mutations in lens crystallins and gap junction proteins constitute the most common genetic alterations causing hereditary congenital cataract. We identified a three-generation family comprising three individuals with congenital cataracts and aphakic glaucoma, one of whom also had microphthalmia, in the UCSF glaucoma clinic. The purpose of this study was to identify the causative mutation in this family and investigate its pathogenesis.
The institutional review board at UCSF approved this study and written informed consent was obtained from all participants or their parents for children under 18 years of age. Subjects provided peripheral venous blood samples or saliva samples for genomic DNA extraction. Exome sequencing was performed on a single affected patient’s sample and filtering strategies were employed to identify the putative mutation. Segregation of the mutation with the phenotype was confirmed with PCR and DNA sequencing of gap junction alpha 8 (GJA8). A computer model of the mutant protein was generated based on the crystal structure of homolog GJB2.
Exome sequencing revealed a novel mutation in GJA8, c.658A>G resulting in a missense mutation p.Asn220Asp in transmembrane domain IV, that was found to segregate with the disease. Computer modeling of the mutant protein showed that this position is critical for interactions between transmembrane helices.
We report the first mutation identified in transmembrane domain IV of GJA8. The mutation showed an autosomal dominant inheritance pattern with reduced penetrance and variable expressivity of the cataract and microphthalmia phenotypes. The pathogenic mechanism may differ from mutations occurring in other domains, which often misfold and fail to form gap junctions. This mutation may instead alter gap junction channel permeability similar to a GJB2 mutation associated with deafness.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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