Metabolic Brain Disease

, Volume 33, Issue 2, pp 589–600 | Cite as

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

  • Ashish Kumar Agrahari
  • P. Sneha
  • C. George Priya Doss
  • R. Siva
  • Hatem Zayed
Original Article


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.


Missense mutations PRPS1 CMTX5 Pathogenicity Stability Molecular dynamics simulation 



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).

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Supplementary material

11011_2017_121_MOESM1_ESM.docx (2 mb)
ESM 1 (DOCX 2084 kb)


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Integrative Biology, School of Biosciences and TechnologyVIT UniversityVelloreIndia
  2. 2.Department of Biomedical Sciences, College of Health and SciencesQatar UniversityDohaQatar

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