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. 2018 May 1;32(10):1661-1668.
doi: 10.1038/s41433-018-0154-8.

Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract

Vanita Berry  1 , Alexander C W Ionides  2 , Nikolas Pontikos  3   4 , Ismail Moghul  5 , Anthony T Moore  2   6 , Michael E Cheetham  3 , Michel Michaelides  7   8
Affiliations

Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract

Vanita Berry et al. Eye (Lond). .

Abstract

Purpose: Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family.

Methods: Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree.

Results: A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH2-terminal region of the gap junction protein GJA3 and found to co-segregate with disease.

Conclusion: We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Abridged pedigree of the British family with lamellar cataract. Squares and circles symbolize males and females, respectively. Open and filled symbols indicate unaffected and affected individuals
Fig. 2
Fig. 2
Sequence analysis of GJA3. An unaffected individual (upper chromatogram illustrates a normal control and a missense mutation c.7 G > T shown in affected member of the family with lamellar cataract
Fig. 3
Fig. 3
Structure of the GJA3 protein. a Transmembrane view of GJA3 https://www.rcsb.org/pdb/explore/explore.do?structureId = 2zw3. b View of the GJA3 hemichannel https://swissmodel.expasy.org/repository/uniprot//Q9Y6H8 c Wild-type amino at position 3 (Aspartate) d Mutant amino acid at position 3 (Tyrosine). The side chain of the tyrosine interferes with the hemichannel activity
See this image and copyright information in PMC

References

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