Search

Background : CHARGE syndrome, caused by mutation of CHD7, is inherited in an autosomal dominant manner. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients which is often diagnosed with the assistance of radiologists. Currently, a vast literature exists reporting possible associations between mutations associated with CHARGE syndrome but the structural and functional impact is very less explored. Objectives: Examining the kind of effects of mutations/variations over the protein structure and function using various experimental analyses, sometimes could be time and cost consuming. In this study, we formulated a computational pipeline effectively to analyze the impact of the mutations at a structural and functional level. Methods: A series of computational analysis such as analyzing the pathogenic impact, stability impact and evolutionary impact occurred due to the mutation (201 missense mutations) as the first line of screening. As a final step, molecular dynamics simulation analysis will be carried out for the understanding of the structural impact of the mutation upon the protein. Results:Based on the availability of 3D structure and deleteriousness by in silico prediction methods,two missense mutations P2683 and R2702C were considered for further analysis. Based on Conservation and physiochemical property analysis mutant R2702C was designated as highly deleterious, highly unstable and high functional effect when compared to P2683S. Molecular Dynamics simulation analysis using Gromacs demonstrated higher RMSD and radius of gyration values in 2702C and less compactness than that of the native and P2683S structure. Conclusion: Hence forth, mutant R2702C is determined to have a huge impact to cause CHARGE syndrome in individuals harboring this mutation. [ABSTRACT FROM AUTHOR]