Investigating the Structural Impact and Conformational Dynamics of a Sequence Variant (c.242G>A) in TMIE Gene Provoking Usher Syndrome

Usher syndrome (USH) is a retinal autosomal recessive genetic disorder, characterized by congenital severe-to-profound sensorineural hearing loss, retinitis pigmentosa (RP), and rarely vestibular dysfunction. A transmembrane inner ear gene TMIE causing autosomal recessive usher syndrome hearing loss, which may open up interesting perspectives into the function of this protein in inner ear. This disease is linked with mutations in TMIE gene. In this study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.242G>A) resulting into (p.Arg81His) in TMIE gene segregating usher syndrome through a molecular dynamics simulations approach. The transmembrane inner ear expressed protein assumes a critical role as its helices actively engage in binding with specific target DNA base pairs. The alteration observed in the mutant protein, characterized by an outward repositioning of the proximal helical portion, which is attributed to the absence of preceding beta-hairpins in the C-terminal region. This structural modification results in the loss of hydrogen bonds, exposure of hydrophobic residues to the solvent, and a consequential transformation of helices into loops, ultimately leading to functional impairment in the TMIE protein. These notable modifications in the stability and conformation of the mutant protein were verified through essential dynamics analysis, revealing that a point mutation induces distinct overall motions and correlations between proteins, ultimately resulting in usher syndrome. The current study provides insilico evidences of Usher syndrome hearing loss disease as protein folding disorder. The energy calculation also revealed that there is a difference of -251.211Kj/mol which also indicates that the SNP has significantly decreased the stability of protein consequently folding into Usher syndrome. This study contributes molecular insights into the structural correlation between the TMIE protein and usher syndrome. The docking analysis highlight various interaction between wild and mutant structure emphasizing key residues involved in hydrogen and hydrophobic interaction.