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

• Published in: Metabolic brain disease Vol. 33; no. 2; pp. 589 - 600
• Main Authors: Agrahari, Ashish Kumar, Sneha, P., George Priya Doss, C., Siva, R., Zayed, Hatem
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2018; Springer Nature B.V
• Subjects: Amino Acid Sequence; Ataxia - genetics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - diagnosis; Charcot-Marie-Tooth Disease - genetics; Colorectal carcinoma; Computational neuroscience; Computer applications; Computer simulation; Covariance matrix; Deaf-Blind Disorders - genetics; Deafness; Disease; Free energy; Genetic Diseases, X-Linked - genetics; Humans; Metabolic Diseases; Missense mutation; Molecular dynamics; Mutation; Mutation - genetics; Neurological diseases; Neurology; Neuropathy; Neurosciences; Oncology; Original Article; Pathogenicity; Pathogens; Phenotype; Phosphoribosyl pyrophosphate; Precision medicine; Predictions; Principal components analysis; Protein structure; Proteins; Ribose-Phosphate Pyrophosphokinase - deficiency; Ribose-Phosphate Pyrophosphokinase - genetics; Salvage; Secondary structure; Stability analysis; Structural analysis; Structural stability; Trajectory analysis; Missense mutations; Pathogenicity; PRPS1; CMTX5; Stability; Molecular dynamics simulation
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-017-0121-2

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.