T8M mutation in connexin-26 impairs the connexon topology and shifts its interaction paradigm with lipid bilayer leading to non-syndromic hearing loss

Approximately, two third cases of non-syndromic deafness are caused by mutation in GJB2; which encodes a β-class gap-junction protein, connexin-26 (Cx26). Cx26 is expressed in cochlea, inner ear and epidermis. It plays an important role in the process of sound transduction through cochlea by permitting the distribution of ions and second messengers (cAMP and inositol 1,4,5-triphosphate (IP3)) through adjacent cells. Any damage in Cx26 structure may disturb the equilibrium of auditory cells and underlying auditory neurotransmission of ions through cochlea which results in partial or complete hearing loss. Current study establishes the use of in-silico approaches to characterize a known deafness-associated frameshift mutation (T8M) in Cx26. The Ca2 + ion interactions were comparatively evaluated in Cx26WT and Cx26T8M structures. Clearly, more stable interactions of Cx26WT were observed with Ca2 + as compared to Cx26T8M, indicating significant changes in the connexon-membrane topology of Cx26T8M. We observed noteworthy differences in Cx26T8M-based tunnel formation and pore characteristics as well as structural differences which may affect release of Ca2 + ions. Thus disturbance in ionic concentration may dysfunction the cochlear hair cells leading to non-syndromic deafness.