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Investigating the role of single nucleotide polymorphisms in human retinoid x receptor gene – a computational approach

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posted on 2022-11-04, 02:31 authored by Soumalya SarkarSoumalya Sarkar

Alterations in signalling of nuclear receptors such as retinoid x receptor (RXRs) are inculpated in several neurodegenerative disorders like glaucoma, Alzheimer’s, Parkinson’s, stroke and multiple sclerosis. Moreover, single nucleotide polymorphisms (SNPs) remain the main cause behind single nucleic acid variations determining heterogeneity within various populations. This study investigated the destructive SNPs which might alter the structural stability, flexibility and role of various RXR isoforms through a computational and molecular modelling approach. Amongst 1,813 retrieved and analysed SNPs several were found to be deleterious with rs140464195_G139R, rs368400425_R358W and rs368586400_L383F RXRα mutants being the most detrimental ones causing changes in interatomic interactions and decreasing the flexibility of the mutant proteins. Molecular genetics analysis identified 7 missense mutations in RXRα/β/γ isoform genes. Two novel mutations SNP IDs (rs1588299621_S224N and rs1057519958_S427Y/F) were identified in RXRα isoform. Several computational algorithmic tools namely SIFT, PolyPhen 2.0, I-Mutant 3.0, PROVEAN, PANTHER, PhD-SNP, SNP&Go, and SNPeffect were deployed to predict pathogenicity and protein stability associated with RXR mutations. Structural assessment by DynaMut revealed that hydrogen bonds were affected along with hydrophobic and carbonyl interactions resulting in reduced flexibility at the mutated residue positions but ultimately stabilizing the molecule as a whole. Summarizing, analysis of the missense mutations in RXR isoforms showed a mix of conclusive and inconclusive genotype-phenotype correlations suggesting use of sophisticated computational analysis tools for studying RXR variants.


Table of Contents

Chapter I - 1. Introduction and Retinoid X Receptor -- Chapter II - 2. Materials and Methods -- Chapter III - 3. Results -- Chapter IV - 4. Discussion -- 5. Conclusion -- 6. Clinical Trials and Future Perspective -- 7. References -- 8. Peer-reviewed publications -- 9. Appendices

Awarding Institution

Macquarie University

Degree Type

Thesis MRes


Thesis (MRes), Macquarie University, Faculty of Medicine, Health and Human Sciences, 2021

Department, Centre or School

Department of Clinical Medicine

Year of Award


Principal Supervisor

Vivek K. Gupta

Additional Supervisor 1

Nitin Chitranshi

Additional Supervisor 2

Stuart L. Graham


Copyright: Soumalya Sarkar Copyright disclaimer:




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