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RESEARCH ARTICLE

Open Access

Identification and functional analysis of a novel missense mutation in GJA8, p.Ala69Thr Dandan Li1†, Chenjia Xu2†, Dandan Huang3, Ruru Guo2, Jian Ji2 and Wei Liu2*

Abstract Background: To explore the molecular genetic cause of a four-generation autosomal dominant congenital cataract family in China. Methods: Targeted region sequencing was performed to screen for the potential mutation, and Sanger sequencing was used to confirm the mutation. The homology model was constructed to identify the protein structural change, PolyPhen-2 and Provean were used to predict the mutation impact. Functional and cellular analysis of the wild and mutant GJA8 were performed in DF-1 cells by western blotting, dye uptake assay, immunofluorescence, Annexin VFITC staining. Results: A novel heterozygous mutation (c.205G > A; p.Ala69Thr) was identified within GJA8, which cosegregated with congenital cataract phenotype in this family. Bioinformatics analysis showed the mutation was located in a highly conserved region, and the mutation was predicted to be pathogenic. Function analysis indicated that the mutation inhibited GJA8 hemichannel activity, reduced cell tolerance to oxidative stress, changed the protein distribution pattern and inhibited the cell growth. Conclusions: We have identified a novel missense mutation in GJA8 (c.205G > A, p.Ala69Thr) in a four-generation Chinese family and our results will further broaden the gene mutation spectrum of GJA8. Keywords: GJA8, Congenital cataract, Hemichannel

Background Congenital cataract is defined as a type of lens opacification that occurs at birth or at an early age, which could damage the vision development. It is estimated that the global prevalence of congenital cataract is 4.24 per 10, 000 live births [1]. In industrialized countries, the prevalence of congenital cataract is 1 to 6 per 10,000, while in * Correspondence: [email protected] † Dandan Li and Chenjia Xu contributed equally to this work. 2 Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Nankai District, Tianjin 300384, China Full list of author information is available at the end of the article

China, the prevalence of congenital cataract is about 5 cases per 10,000 [2]. The incidence of congenital cataract is related to many factors, and hereditary factor is the most important one and responsible for the majority of cases [3–5]. The most common genetic pattern of congenital cataract is autosomal dominant, and there are also reports of autosomal recessive and Xlinked forms. The known mutant genes responsible for congenital cataracts include lens membrane proteins (GJA3, GJA8, MIP), crystallins (CRYAA, CRYAB, CRYBA1/A3, CRYBA4, CRYBB1, CRYBB2, CRYGC, CRYGD and CRYGS), cytoskeletal proteins (BFSP1, BFSP2), growth and transcription factors (HSF4) and others [6–11]. Among these mutant genes, t

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