Abstract
Introduction
Hakhamanesh Behmanesh, Hamza Khan, Jubin Kim, Neha Deo, Ting-An Cheng
The University of British Columbia, Vancouver, BC 4
References
[1] Holloway et al. Detection of Interruptions in the GAA Trinucleotide Repeat Expansion in the
FXN Gene of Friedreich Ataxia, Hum Mol Genet. 2013, 22(25): 5173–5187
[2] Singh, HN, and MR Rajeswari. Role of Long Purine Stretches in Controlling the Expression
of Genes Associated with Neurological Disorders, Gene 2015, 572(2): 175-83
[3] Kumar et al. Computational SNP Analysis: Current Approaches and Future Prospects, Cell
Biochem Biophys. 2014, 68(2):233-9
[4] Pandolfo at al., Friedreich Ataxia: Detection of GAA Repeat Expansions and Frataxin Point
Mutations. Methods in molecular medicine 2006, 126:197-216
[5] Berendsen, et al. GROMACS, Comp. Phys. Comm. 1995, 91: 43-56
Computational and structural analysis of non-synonymous single
nucleotide polymorphisms in human FXN (frataxin) gene
 Friedreich ataxia is an autosomal recessive neurodegenerative disease that occurs mostly
due to the expansion of GAA trinucleotide repeats in the first intron of FXN gene.1Although
little is understood about the causation of Friedreich ataxia, recent studies suggest that
point mutations may be involved in Friedreich ataxia patients2
 With a total of 95 non-synonymous single nucleotide polymorphisms (nsSNPs) reported for
FXN gene on the Single Nucleotide Polymorphism Database (dbSNP), this study provides
structural and functional insight into the effect of these nsSNPs on the stability and activity
of mutant frataxin protein
 The harmfulness of these nsSNPs were evaluated using eight different computational
approaches such as I-mutant, SIFT, Polyphen2, SNP & GO, Mutpred, etc. Deleterious
nsSNPs were prioritized and further evaluated for protein stability changes
 Protein crystal structure for frataxin protein was obtained from protein data bank (PDB),
while the mutant protein was modelled using homology modelling. GROMACS (Groningen
machine for chemical simulations) was used to simulate native and mutant protein
structures over time
 Structural and functional changes were determined by examining several protein
characteristics, such as hydrogen bonds, solvent accessibility surface area, root mean
square deviations, root mean square fluctuations, etc. over a fixed time interval. Our
analysis of these nsSNPs would provide a basis for understanding the effects of functional
nsSNPs and their role in causing Friedreich ataxia
Figure 1. Friedreich’s ataxia(FRDA) is an
autosomal recessive neurodegenerative
disorder which causes muscle weakness,
scoliosis, absent limb reflexes, etc.
Figure 3. FRDA is known to be caused by
GAA repeat in FXN gene’s intron resulting
in FXN silencing
Figure 2. FXN gene codes for protein frataxin
which is found in mitochondria and appears to
assemble iron and sulfur cluster
Figure 4. nsSNP might influence the protein
stability of Frataxin and can be evaluated
through in-silico tools and Molecular Dynamic
Simulation
Black – Native protein
Red – Mutant protein
Ramachandran plot for the modelled protein
Methodology
Results
https://www.mda.org/disease/friedreichs-ataxia
Molecular dynamics and simulation results for
L106S
Number of residues in favoured region (~98.0% expected) : 118 (99.2%)
Number of residues in allowed region (~2.0% expected) : 1 (0.8%)
Number of residues in outlier region : 0 (0.0%)
Computational SNP analysis

URO117_Poster (1)

  • 1.
    Abstract Introduction Hakhamanesh Behmanesh, HamzaKhan, Jubin Kim, Neha Deo, Ting-An Cheng The University of British Columbia, Vancouver, BC 4 References [1] Holloway et al. Detection of Interruptions in the GAA Trinucleotide Repeat Expansion in the FXN Gene of Friedreich Ataxia, Hum Mol Genet. 2013, 22(25): 5173–5187 [2] Singh, HN, and MR Rajeswari. Role of Long Purine Stretches in Controlling the Expression of Genes Associated with Neurological Disorders, Gene 2015, 572(2): 175-83 [3] Kumar et al. Computational SNP Analysis: Current Approaches and Future Prospects, Cell Biochem Biophys. 2014, 68(2):233-9 [4] Pandolfo at al., Friedreich Ataxia: Detection of GAA Repeat Expansions and Frataxin Point Mutations. Methods in molecular medicine 2006, 126:197-216 [5] Berendsen, et al. GROMACS, Comp. Phys. Comm. 1995, 91: 43-56 Computational and structural analysis of non-synonymous single nucleotide polymorphisms in human FXN (frataxin) gene  Friedreich ataxia is an autosomal recessive neurodegenerative disease that occurs mostly due to the expansion of GAA trinucleotide repeats in the first intron of FXN gene.1Although little is understood about the causation of Friedreich ataxia, recent studies suggest that point mutations may be involved in Friedreich ataxia patients2  With a total of 95 non-synonymous single nucleotide polymorphisms (nsSNPs) reported for FXN gene on the Single Nucleotide Polymorphism Database (dbSNP), this study provides structural and functional insight into the effect of these nsSNPs on the stability and activity of mutant frataxin protein  The harmfulness of these nsSNPs were evaluated using eight different computational approaches such as I-mutant, SIFT, Polyphen2, SNP & GO, Mutpred, etc. Deleterious nsSNPs were prioritized and further evaluated for protein stability changes  Protein crystal structure for frataxin protein was obtained from protein data bank (PDB), while the mutant protein was modelled using homology modelling. GROMACS (Groningen machine for chemical simulations) was used to simulate native and mutant protein structures over time  Structural and functional changes were determined by examining several protein characteristics, such as hydrogen bonds, solvent accessibility surface area, root mean square deviations, root mean square fluctuations, etc. over a fixed time interval. Our analysis of these nsSNPs would provide a basis for understanding the effects of functional nsSNPs and their role in causing Friedreich ataxia Figure 1. Friedreich’s ataxia(FRDA) is an autosomal recessive neurodegenerative disorder which causes muscle weakness, scoliosis, absent limb reflexes, etc. Figure 3. FRDA is known to be caused by GAA repeat in FXN gene’s intron resulting in FXN silencing Figure 2. FXN gene codes for protein frataxin which is found in mitochondria and appears to assemble iron and sulfur cluster Figure 4. nsSNP might influence the protein stability of Frataxin and can be evaluated through in-silico tools and Molecular Dynamic Simulation Black – Native protein Red – Mutant protein Ramachandran plot for the modelled protein Methodology Results https://www.mda.org/disease/friedreichs-ataxia Molecular dynamics and simulation results for L106S Number of residues in favoured region (~98.0% expected) : 118 (99.2%) Number of residues in allowed region (~2.0% expected) : 1 (0.8%) Number of residues in outlier region : 0 (0.0%) Computational SNP analysis