Computer simulations reveal pathogenicity and inheritance modes of hearing loss-causing germinal variants

Variants in the gap junction beta-2 ( GJB2 ) gene are the most common cause of hereditary hearing impairment. However, how GJB2 variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In the present study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal “plugs” aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homomeric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable heteromeric channels did not. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found in Gjb2 V37M/V37M outer sulcus cells and Claudius cells but not in Gjb2 WT/WT cells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance of GJB2 -related hearing impairments and other diseases caused by connexin dysfunction. ### Competing Interest Statement The authors have declared no competing interest.