Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative fatal disease that can affect the neurons of brain and spinal cord. ALS genetics has identified various genes to be associated with disease pathology. Oxidative stress induced bunina and lewy bodies formation can be regulated through the action of SOD1 protein. Hence, in the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putative correlation with the location of mutation and degree of ALS severity by inferring the structural and functional alterations in different SOD1 variants.MethodsWe have retrieved around 69 SNPs of SOD1 gene from Genecards. Structural annotation of SOD1 variants were performed using SWISS Model, I-Mutant 2.0, Dynamut, ConSurf. Similarly, the functional annotation of same variants were done using SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB. Ramachandran plot was also obtained for six synonymous SNPs to compare the amino acid distribution of wild-type SOD1 (WT SOD1) protein. Frequency analysis, Chi square analysis, ANOVA and multiple regression analysis were performed to compare the structural and functional components among various groups.Results and conclusionResults showed the mutations in conserved domain of SOD1 protein are more deleterious and significantly distort the tertiary structure of protein by altering Gibb’s free energy and entropy. Moreover, significant changes in SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB scores were also observed in mutations located in conserved domain of SOD1 protein. Multiple regression results were also suggesting the significant alterations in free energy and entropy for conserved domain mutations which were concordant with structural changes of SOD1 protein. Results of the study are suggesting the biological importance of location of mutation(s) which may derive the different disease phenotypes and must be dealt accordingly to provide precise therapy for ALS patients.
Highlights
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease), a term coined by Jean Martin Charcot in 1874, is considered to be one of the most fatal neurodegenerative diseases
The present study aims to examine the changes in functional and structural domains of SOD1 protein for the reported SNPs in various studies
Frequency and association of SOD1 variants Studied exonic mutations are mostly falling in conserved domain (49 variants) of SOD1 protein which have been found to affect the protein structure (52 variants) and show deleterious effect (62 variants) on SOD1 protein in ALS pathology (Table 5)
Summary
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease), a term coined by Jean Martin Charcot in 1874, is considered to be one of the most fatal neurodegenerative diseases. Mutations in 13 genes and their loci have been identified as the causal genetic factor for typical ALS clinical phenotype which primarily involves SOD1, TARDBP, ANG, FUS, and OPTN etc. Hexa-nucleotide expansion (G4C2) of C9ORF72 gene (by mean of loss or gain of function mutations leading to develop somatic mosaicism) has been associated with fALS (with 3.2% prevalence rate in Indian ALS) which may stimulate pathology by TDP-43 accumulation, impaired RNA metabolism and defective proteosomal degradation mechanism [10,11,12]. In the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putative correlation with the location of mutation and degree of ALS severity by inferring the structural and functional alterations in different SOD1 variants
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