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A profound computational study to prioritize the disease-causing mutations in PRPS1 gene.
Ashish Kumar Agrahari1, P Sneha1, C George Priya Doss2
1Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India.
Metabolic Brain Disease
|October 20, 2017
Summary
This study investigates PRPS1 gene mutations linked to Charcot-Marie-Tooth disease (CMT). Computational analysis identified four mutations potentially causing disease by affecting protein stability and function, aiding personalized medicine approaches.
Area of Science:
- Genetics and Molecular Biology
- Computational Biology and Bioinformatics
- Neurology
Background:
- Charcot-Marie-Tooth disease (CMT) is a common inherited neurological disorder affecting 1 in 2500 individuals in the US.
- Mutations in the phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene are associated with various conditions, including X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5).
- Understanding the impact of PRPS1 mutations is crucial for developing targeted therapies.
Purpose of the Study:
- To computationally assess the pathogenicity and stability of missense mutations in the PRPS1 gene.
- To investigate the structural and functional consequences of specific PRPS1 mutations using molecular dynamics simulations.
- To provide a basis for drug repositioning and personalized medicine for PRPS1-deficiency related diseases.
Main Methods:
- Collected 20 missense mutations from UniProt and dbSNP databases.
- Employed in silico prediction tools to identify potential disease-causing mutations.
- Performed 50 ns molecular dynamics simulations (MDS) on four identified mutations and the native PRPS1 protein using Gromacs.
- Analyzed simulation data using RMSD, Rg, SASA, Covariance matrix, PCA, FEL, and secondary structure analysis.
Main Results:
- In silico analysis predicted four missense mutations (D52H, M115T, L152P, D203H) as potentially pathogenic.
- Molecular dynamics simulations revealed that these four mutations may alter the stability and structure of the PRPS1 protein.
- Structural changes suggest a potential impact on PRPS1 protein function.
Conclusions:
- The identified PRPS1 mutations (D52H, M115T, L152P, D203H) are predicted to affect protein stability and function.
- This research offers a computational framework for understanding PRPS1-related disorders.
- Findings support potential applications in drug repositioning and personalized medicine for diseases linked to PRPS1 deficiency.
