Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10)

Abstract

Bardet-Biedl Syndrome (BBS) is a rare inherited disorder resulting in multiple organ dysfunctions, whose cardinal clinical features include cognitive impairment, obesity, and renal dysfunction. Although it is highly heterogeneous at genetic levels, BBS10 is one of the major causative genes worldwide. The BBS10 protein is part of a multiprotein complex localized at the basal body of the primary cilium. With the advancement of sequencing technologies, novel missense mutations are regularly reported in BBS10. However, prioritizing missense variants and conducting further in-depth analysis are key challenges in addressing their pathogenic effect. This study aims to characterize the known missense mutations of BBS10 by combining nine different in silico tools (SIFT, SNAP2, PROVEAN, Align-GVGD, ConSurf, I Mutant, MuPro, PremPS, and Dynamut) and molecular dynamics (MD) simulations. A total of 101 BBS10 missense variants have been analyzed. Our results showed that six BBS10 missense variants (Ser191Leu, Cys19Gly, Ile342Thr, Cys371Ser, Ala417Glu, and Tyr613Cys) were potentially deleterious. Overall, this study provides a comprehensive workflow for screening BBS10 missense mutations to identify pathogenic variants effectively.

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

“…Multiple in silico tools predicted that Case 2 and Case 3 harbor pathogenic missense variants as pathogenic; similar tools have also been utilized to predict pathogenic variants of other genes related to kidney disorders [ 34 ]. Case 2 showed the hemizygous missense c.991G>A p.Gly331Ser COL4A5 (NM_000495) variant.…”

Evaluation of Pathogenicity and Structural Alterations for the Mutations Identified in the Conserved Region of the C-Terminal Kinase Domain of Human-Ribosomal S6 Kinase 1

“…Recent advancement in in silico pathogenicity prediction tools has eased the process of screening large mutational data to prioritize and validate mutations using structural and functional aspects. 18 − 20 Moreover, molecular dynamics simulation is a computational approach to explore the structural changes in protein structure brought about by mutation. In addition, these investigations contribute to the understanding of how mutations affect protein–protein interactions, folding pattern, and ligand binding for targeted drug design.…”

“…Recent advancement in in silico pathogenicity prediction tools has eased the process of screening large mutational data to prioritize and validate mutations using structural and functional aspects. − Moreover, molecular dynamics simulation is a computational approach to explore the structural changes in protein structure brought about by mutation. In addition, these investigations contribute to the understanding of how mutations affect protein–protein interactions, folding pattern, and ligand binding for targeted drug design. − Therefore, after screening the pathogenicity using different in silico tools, molecular dynamics (MD) simulation was performed to gain more insights into the effect of mutations on protein structure and dynamics. − The CTKD plays a crucial role in RSK1 activation.…”