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

Berry, Vanita; Ionides, Alexander; Pontikos, Nikolas; Moghul, Ismail; Moore, Anthony T.; Cheetham, Michael E.; Michaelides, Michel

doi:10.1038/s41433-018-0154-8

Cited by 6 publications

(2 citation statements)

References 36 publications

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“…To date, more than 50 mutations in the diverse domains of Cx46 have been identi ed in contributing to human inherited cataracts in various ethnic groups (28). Cx46 mutations are phenotypically extremely heterogeneous (29). Most of the mutations in the Cx46 gene associated with CC are located in the extracellular loop and transmembrane domains (Fig.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identified a novel missense variant in the connexin 46 (GJA3) gene causing congenital cataract in an Iranian pedigree

Ranjbarrad¹,

Jebelli²,

Sadeghi³

et al. 2022

Preprint

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Background: Congenital cataract (CC) is the most common reason for visual loss and blindness at birth or early childhood worldwide. The autosomal dominant (AD) inheritance is reported as the most frequent transmission pattern for CC. Connexin 46 (Cx46 coded by GJA3 gene) belongs to the gap junction proteins family which has the main function in the cell communication system of the eye lens. Methods: In the present research, whole-exome sequencing (WES) was done for proband diagnosed by CC, and Co-segregation analysis using Sanger sequencing was performed for the candidate variant on healthy and affected family members. The candidate variant was analyzed with appropriate bioinformatics software and then classified according to the ACMG guideline. Results: WES analysis of proband recognized a novel heterozygous c.146 A>C (p.Q49P) variant in the exon 2 of the GJA3 gene leading to the substitution of a highly conserved Glutamine by Proline at codon 49. The linkage of CC with this variant was observed for three generations in a proband family with AD inheritance. This variant is located on phylogenetically conserved extracellular loop E1 of protein. Extracellular loops play the main role to mediate hemichannel docking between connexons and regulating voltage gating of the channel. Conclusion: Our finding emphasized the role of Cx46 in the pathogenesis of ADCC and the extended mutation spectrum of the GJA3 gene in association with CC.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identified a novel missense variant in the connexin 46 (GJA3) gene causing congenital cataract in an Iranian pedigree

Ranjbarrad¹,

Jebelli²,

Sadeghi³

et al. 2022

Preprint

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“…Cx46 and Cx50 colocalize at gap junction plaques and form mixed hexamers [1,2]. Accumulating evidence demonstrates that congenital dysfunction of the GJA3 gene is an important genetic risk factor in autosomal dominant congenital cataracts (ADCCs) [3][4][5], strongly supporting their close relationship with maintenance of lens transparency [6].…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the human GJA3 gene associated with congenital cataract

Zhang

Huang

Wang

et al. 2020

BMC Mol and Cell Biol

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Background: Gap junction protein alpha 3 (GJA3), an important pathogenic gene of congenital cataracts, encodes the transmembrane protein connexin46, which functions as an intercellular channel for voltage and chemical gating by forming dodecamers. This study systematically collected nsSNP information for the GJA3 gene from SNP databases and literature and screened for nsSNPs with high risks of pathogenicity. Results: A total of 379 nsSNPs of GJA3 were identified. A total of 88 high-risk pathogenic GJA3 nsSNPs were found, including 31 published nsSNPs associated with congenital cataracts and 57 novel nsSNPs predicted by all eight online tools. The 88 high-risk pathogenic mutations, which are related to 67 amino acids in the wild-type sequences, cause a decrease in protein stability according to I-Mutant 3.0, MUpro and INPS. G2 and R33 were predicted to participate in post-translational modification and ligand binding by ModPred, RaptorX Binding and COACH. Additionally, high-risk mutations were likely to involve highly conserved sites, random coils, alpha helixes, and extracellular loops and were accompanied by changes in amino acid size, charge, hydrophobicity and spatial structure. Conclusions: Eighty-eight high-risk pathogenic nsSNPs of GJA3 were screened out in the study, 57 of which were newly reported. The combination of multiple in silico tools is highly efficient for targeting pathogenic sites.

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Molecular genetics of congenital cataracts

Chen

Yan

et al. 2020

Experimental Eye Research

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

Cited by 6 publications

References 36 publications

Whole-exome sequencing identified a novel missense variant in the connexin 46 (GJA3) gene causing congenital cataract in an Iranian pedigree

Whole-exome sequencing identified a novel missense variant in the connexin 46 (GJA3) gene causing congenital cataract in an Iranian pedigree

In silico analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the human GJA3 gene associated with congenital cataract

Molecular genetics of congenital cataracts

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