Rare missense variants in <i>MYO7A</i> and <i>OTOP2</i> genes in a South Korean Meniere’s disease cohort

Background Meniere’s disease (MD) is a polygenic condition defined by episodes of vertigo associated with sensorineural hearing loss and tinnitus. Genetic studies in familial MD in East Asian populations are limited, and the potential MD genes remain to be established in non-Finnish European populations. Methods By exome sequencing and rare variant analysis, we have searched for existing and novel genes associated with MD in a South Korean cohort of 16 MD individuals with bilateral sensorineural hearing loss. Results We have found one individual with two rare missense variants in the OTOP2 gene, a new candidate gene for MD and three heterozygous variants in the MYO7A gene, supporting the hypothesis of biallelic inheritance. Wild-type and mutated protein models were compared, and currents were measured in the human proton channel OTOP2 expressed in Xenopus laevis oocytes to further elucidate functional consequences. Structural changes in the T364M or H435Q OTOP2 variants were not associated with changes in measured currents, regardless of pH or Ca 2+ concentrations. Conclusion The OTOP2 gene is a novel candidate for the audiovestibular dysfunction observed in MD. Furthermore, rare variants in the MYO7A gene, previously associated with European MD, have been found in the South Korean cohort. The OTOP2 protein was found in the basal cells of the stria vascularis, spiral ganglion neurons and inner hair cells in the organ of Corti, suggesting a dual role in endolymphatic homeostasis and neural signal transmission.