In-silico assessment of the potential impact of missense SNPs in SYNE4 and SUN1 on the LINC complex and their association with hearing loss

Abstract

The LINC complex plays a significant role in the auditory system, as it participates in maintaining proper positioning and survival of the nucleus within the outer hair cells. To investigate the potential effect of mutations on the LINC complex structure and its association with hearing loss, we used a computational approach to analyze missense SNPs in SYNE4 and SUN1 genes, which encode Nesprin4 and SUN1 proteins, respectively. SNPs were collected from the Ensembl database and subsequently subjected to various prediction tools, such as SIFT, Polyphen2, MetaRNN, Mutation Taster, Provean, BayesDel_addAF, M-CAP, and MetaRL. Then, the UCSF chimera was used for the introduction of a corresponding amino acid substitution in each protein. HADDOCK 2.4 executed a molecular docking, the protein–protein interaction was driven by PRODIGY, and the conservation state was determined using ConSurf. Finally, a molecular dynamics simulation using Gromacs (2019.3) software was executed for the LINC complexes that correspond to the most deleterious variants for both genes. Our findings show that specific variants in SYNE4 (C381F) and SUN1 (D735Y, D735G, R761W, and C773R) significantly affect the structural integrity of the LINC complex, leading to observable destabilization. These variants are predicted to have a damaging effect on hearing ability. The bioinformatics tools employed in this study consistently predicted these variants as highly structurally affected. However, further investigations are necessary to establish a more comprehensive understanding of the precise implications of these alterations on human auditory function.