title: Mutational analysis of FUS gene and its structural and functional role in amyotrophic lateral sclerosis 6.
abstract: Amyotrophic lateral sclerosis 6 (ALS6) is an autosomal recessive disorder caused by heterozygous mutation in the Fused in Sarcoma (FUS) gene. ALS6 is a neurodegenerative disorder, which affects the upper and lower motor neurons in the brain and spinal cord, resulting in fatal paralysis. ALS6 is caused by the genetic mutation in the proline/tyrosine-nuclear localization signals of the Fused in sarcoma Protein (FUS). FUS gene also known as TLS (Translocated in liposarcoma), which encodes a protein called RNA-binding protein-Fus (FUS), has a molecular weight of 75 kDa. In this analysis, we applied computational approach to filter the most deleterious and neurodegenerative disease of ALS6-associated mutation on FUS protein. We found H517Q as most deleterious and disease associated using PolyPhen 2.0, I-Mutant 3.0, SIFT, SNPs&GO, PhD-SNP, Pmut, and Mutpred tools. Molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation. MDS results showed the flexibility loss in mutant (H517Q) FUS protein. Due to mutation, FUS protein became more rigid in nature and might alter the structural and functional behavior of protein and play a major role in inducing ALS6. The results obtained from this investigation would help in the field of pharmacogenomics to develop a potent drug target against FUS-associated neurodegenerative diseases.
authors.affiliation: a School of Bio Sciences and Technology (SBST), Bioinformatics Division , Vellore Institute of Technology University , Vellore 632014 , Tamil Nadu , India.
authors.forename: Balu
authors.initials: B
authors.lastname: Kamaraj
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
authors.forename: Rao
authors.initials: R
authors.lastname: Sethumadhavan
authors.forename: Chundi Vinay
authors.initials: CV
authors.lastname: Kumar
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016000:Cluster Analysis; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics*
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS
keywords: flexibility; molecular dynamics simulations; nsSNPs; rigid