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A profound computational study to prioritize the disease-causing mutations in PRPS1 gene

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Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.

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Acknowledgements

We would like to thank VIT University and CDAC@BRAF for providing the facility. Ashish Kumar Agrahari is extremely grateful to Dr. Mitali Mukerji (Senior Principal Scientist at the CSIR Institute of Genomics and Integrative Biology) for the providing the facility at CSIR-IGIB to carrying out the project in generating the secondary structure bar plot (Fig. 1).

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  1. Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India

    Ashish Kumar Agrahari, P. Sneha, C. George Priya Doss & R. Siva

  2. Department of Biomedical Sciences, College of Health and Sciences, Qatar University, Doha, Qatar

    Hatem Zayed

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  1. Ashish Kumar Agrahari
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  2. P. Sneha
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Correspondence to C. George Priya Doss or Hatem Zayed.

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Agrahari, A.K., Sneha, P., George Priya Doss, C. et al. A profound computational study to prioritize the disease-causing mutations in PRPS1 gene. Metab Brain Dis 33, 589–600 (2018). https://doi.org/10.1007/s11011-017-0121-2

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