Computational Analysis of disease Associated SNPs in DJ1 PRKN and VPS35 Genes

Abstract

ABSTRACT newlinesecond most common progressive and chronic neurological newlinedisorder. Clinically, PD is characterized by bradykinesia, rigidity, and resting newlinetremor. Research on the genetics of PD mutations are growing continuously and reported newlineglobally. However, currently six genes, i.e., SNCA, DJ-1, LRRK2, PINK1, VPS35 and newlineParkin, have been link together with autosomal recessive/dominant PD means of newlineheritance.The gene DJ-1, also known as PARK7, is located on chromosome band 1p36 newlineshows involvement in the pathogenesis of PD through various pathways like oxidative injury newlineand mitochondrial dysfunction. PRKN functions as maintaining dopamine (DA) neuronal newlinehomeostasis and homeostasis dysfunction both play an important role in gradual PD onset. newlineThe gene VPS35 is located on the chromosome band 16q13-q21 also shows a connection newlinewith PD pathogenesis via involvement of Wnt signaling and retromer-mediated sorting newline(missorting of DMT1) pathways. The present study primarily focused on identifying the newlinemost deleterious single nucleotide polymorphisms (SNPs) among these three genes (DJ-1, newlinePRKN, and VPS35) through various computational programs. Here, five key algorithms used newlineto predict the complex structure and functional effect of non-synonymous SNPs (nsSNPs) newlineon the genes. The investigation of these genes (DJ-1, PRKN, and VPS35) through diverse newlinebioinformatics tools predicts a deleterious mutation. The gene DJ-1 exhibited only one newlinemutation i.e. D149A as most deleterious; in gene PRKN, twelve SNPs are most deleterious, newlinei.e., A46T, I23T, C212Y, D243N, E28G, G359D, P37L, Q34R, R256C, R275W, R366W, newlineand R402C, and in gene VPS35 only three SNPs are most deleterious, i.e., A54W, R365H, newlineand V717M. Furthermore, the native and the mutant proteins of these genes (DJ-1, PRKN, newlineand VPS35) were modeled through the MODELLER9.15 program and validated via two newlineprograms-Prosa-Web and Rampage. Finally, Molecular dynamics simulation (MDS) was newlinedone and different parametres such as RMSD, RMSF, Rg, SASA, H-Bond and PCA are newlineanalyzed through