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Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy

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Abstract

Background

Synonymous variations have always been ignored while studying the underlying genetic mechanisms for most of the human diseases. However, recent studies have suggested that these silent changes in the genome can alter the protein expression and folding.

Methods and results

CSRP3, which is a well-known candidate gene associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), was screened for 100 idiopathic DCM cases and 100 controls. Three synonymous variations were identified viz., c.96G > A, p.K32=; c.336G > A, p.A112=; c.354G > A, p.E118=. A comprehensive in silico analysis was performed using various web based widely accepted tools, Mfold, Codon Usage, HSF3.1 and RNA22. Mfold predicted structural changes in all the variants except c.96 G > A (p.K32=), however it predicted changes in the stability of mRNA due to all the synonymous variants. Codon bias was observed as evident by the Relative Synonymous Codon Usage and Log Ratio of Codon Usage Frequencies. The Human Splicing Finder also predicted remarkable changes in the regulatory elements in the variants c.336G > A and c.354 G > A. The miRNA target prediction using varied modes available in RNA22 revealed that 70.6% of the target sites of miRNAs in CSRP3 were altered due to variant c.336G > A while 29.41% sites were completely lost.

Conclusion

Findings of the present study suggest that synonymous variants revealed striking deviations in the structural conformation of mRNA, stability of mRNA, relative synonymous codon usage, splicing and miRNA binding sites from the wild type suggesting their possible role in the pathogenesis of DCM, either by destabilizing the mRNA structure, or codon usage bias or else altering the cis-acting regulatory elements during splicing.

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Data Availability

The raw or derived data associated with the present study are available from corresponding author on request.

Code Availability

Not Applicable.

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Acknowledgements

We are grateful to all the patients, their families and control individuals who participated in the present study. We are extremely thankful to Dr. T. K. Lahiri and Dr. Damyanti Agarwal from Department of Cardio-vascular and Thoracic Surgery, IMS, BHU, Varanasi for their constant support and encouragement in recruitment of patients. We acknowledge University Grants Commission–Centre of Advanced Studies (UGC-CAS) for research fellowship to Ms. Prerna Giri.

Funding

This study was financially supported by the Department of Atomic Energy, Board of Research in Nuclear Sciences, Mumbai, India (BRNS No. 2013/37B/28). The funding agency had no role in experimental design, sample collection, analysis and interpretation of data, manuscript preparation and decision to submit the article for publication.

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Authors and Affiliations

  1. Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Prerna Giri & Bhagyalaxmi Mohapatra

  2. Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Dharmendra Jain

  3. Department of Paediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Ashok Kumar

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Contributions

Prerna Giri performed the mutation screening, all the in silico characterization and prepared the original draft including all the figures and table. Dr. Bhagyalaxmi Mohapatra conceptualized the study, acquired funding, critically supervised and revised the manuscript at every single step. Dr. Ashok Kumar and Dr. Dharmendra Jain clinically evaluated and diagnosed patients recruited for the study and also helped in collection of blood samples from patients and their available relatives. All authors read and approved the final manuscript.

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Correspondence to Bhagyalaxmi Mohapatra.

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Giri, P., Jain, D., Kumar, A. et al. Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy. Mol Biol Rep 50, 4105–4117 (2023). https://doi.org/10.1007/s11033-023-08314-7

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