In silico analysis of Single Nucleotide Polymorphisms in human GCH1 gene

Abstract

Introduction: Dopa responsive dystonia (DRD) is an inherited movement disorder. Mutations in GCH1 gene is the most common root of autosomal dominant, early onset of DRD. This study aimed to analyze the genetic variation that can alter the expression and the function of the GCH1 gene using computational methods. Materials and methods: All SNPs were retrieved from the dbSNP database. GeneMANIA software was used to show gene-gene interaction. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) were analyzed using different tools (SIFT, PolyPhen-2, PROVEAN, SNPs & GO, I-Mutant, MUpro, Swiss-PdbViewer and Project HOPE). The SNPs in 3′UTR and 5′UTR regions were analyzed using PolymiRTs and SNP Function Prediction tools, respectively. Results: According to dbSNP database, the human GCH1 gene contained 178 SNPs in the coding region, 451 in the 3′ UTR and 63 in the 5′ UTR. GeneMania revealed that GCH1 had strong interactions with other genes involved in phenol-containing compound and catecholamine biosynthetic process, regulation of monooxygenase activity and nitric-oxide synthase activity. A total of seven nsSNPs (R88W, G108D, D134V, G201E, H144P, I135K and R184H) were predicted to have the most damaging effects on structure, function and affecting the GCH1 protein stability. Modeling was done using Project HOPE and Swiss-PdbViewer. Regarding the non-coding region, 33 SNPs out of 451 in 3′UTR were predicted by PolymiRTs to induce disruption or creation of miRNA binding sites while two SNPs were predicted by SNP Function Prediction to be functionally significant in the 5′ UTR. Conclusion: Functional and structural impacts of SNPs in the GCH1gene were studied using computational prediction tools. Pathogenic SNPs predicted in this study can be considered as important candidates inducing Dopa responsive dystonia and could be used as diagnostic markers.

Keywords

• DRD
• GCH1gene
• Insilco analysis
• Segawa syndrome
• SNPs