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: Balu Kamaraj, Vidya Rajendran, Rao Sethumadhavan, Chundi Vinay Kumar, Rituraj Purohit
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 33 Issue 4 Pg. 834-44 ( 2015) ISSN: 1538-0254 [Electronic] England
• PMID: 24738488 (Publication Type: Journal Article)

Chemical References

• FUS protein, human
• RNA-Binding Protein FUS

Topics

• Amyotrophic Lateral Sclerosis (genetics)
• Cluster Analysis
• Humans
• Hydrogen Bonding
• Molecular Dynamics Simulation
• Mutation, Missense
• Polymorphism, Single Nucleotide
• Protein Structure, Secondary
• RNA-Binding Protein FUS (chemistry, genetics)