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

Mingzhou Zhang,Zhenyu Wang,Xuemin Li,Huibin Lv,Chen Huang

doi:10.1186/s12860-020-00252-7

Mingzhou Zhang, Zhenyu Wang + Show 3 more

Open Access

https://doi.org/10.1186/s12860-020-00252-7

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Abstract

BackgroundGap 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.ResultsA 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.ConclusionsEighty-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.

Highlights

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
The present study aims to combine use of several in silico tools that based on different principles to investigate the potentially detrimental effects of Non-synonymous single nucleotide polymorphism (nsSNP) of the GJA3 gene
Results nsSNP retrieval Four databases were searched by the keyword “GJA3”, and the dbSNP database contained the most nsSNPs (353), followed by the Human gene mutation database (HGMD) (31), the ClinVar database (28), and the DisGeNET database (12)

Summary

Introduction

Gap junction protein alpha 3 (GJA3), an important pathogenic gene of congenital cataracts, encodes the transmembrane protein connexin, 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. Gap junctions, formed by docking between lens cells, are responsible for intercellular communication. 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]. Cx46 functions as an intercellular channel for voltage and chemical gating [9]. After the Gja gene is knocked out, mice present with high calcium influx and dramatically decreasing glutathione in the nucleus, leading to

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