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Simulation Based Investigation of Deleterious nsSNPs in ATXN2 Gene and Its Structural Consequence Toward Spinocerebellar Ataxia
Author(s) -
Sinha Siddharth,
Verma Sharad,
Singh Aditi,
Somvanshi Pallavi,
Grover Abhinav
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26209
Subject(s) - spinocerebellar ataxia , genetics , mutant , biology , gene
Spinocerebellar degeneration, termed as ataxia is a neurological disorder of central nervous system, characterized by limb in‐coordination and a progressive gait. The patient also demonstrates specific symptoms of muscle weakness, slurring of speech, and decreased vibration senses. Expansion of polyglutamine trinucleotide (CAG) within ATXN2 gene with 35 or more repeats, results in spinocerebellar ataxia type‐2. Protein ataxin‐2 coded by ATXN2 gene has been reported to have a crucial role in translation of the genetic information through sequestering the histone acetyl transferases (HAT) resulting in a state of hypo‐acetylation. In the present study, we have evaluated the outcome for 122 non synonymous single nucleotide polymorphisms (nsSNPs) reported within ATXN2 gene through computational tools such as SIFT, PolyPhen 2.0, PANTHER, I‐mutant 2.0, Phd‐SNP, Pmut, MutPred. The apo and mutant (L305V and Q339L) form of structures for the ataxin‐2 protein were modeled for gaining insights toward 3D spatial arrangement. Further, molecular dynamics simulations and structural analysis were performed to observe the brunt of disease associated nsSNPs toward the strength and secondary properties of ataxin‐2 protein structure. Our results showed that, L305V is a highly deleterious and disease causing point substitution. Analysis based on RMSD, RMSF, Rg, SASA, number of hydrogen bonds (NH bonds), covariance matrix trace, projection analysis for eigen vector demonstrated a significant instability and conformation along with rise in mutant flexibility values in comparison to the apo form of ataxin‐2 protein. The study provides a blue print of computational methodologies to examine the ataxin‐blend SNPs. J. Cell. Biochem. 119: 499–510, 2018. © 2017 Wiley Periodicals, Inc.