Deficiency of sphingomyelin synthase‐1 but not sphingomyelin synthase‐2 causes hearing impairments in mice

Key points • Sphingomyelin (SM) is a structural component of plasma membrane and may participate in signal transduction. The role of SM metabolism in hearing remains controversial. • Here we examined hearing in mice deficient of SM synthase‐1 (SMS1) or SMS2, and show that only deficiency of SMS1 causes hearing loss. • The hearing loss in SMS1 knockout mice is attributable at least in part to a reduction of endocochlear potential. • The reduction of endocochlear potential is attributable at least in part to atrophy of the cochlear stria vascularis and its altered expression of K+ channels. • Our results establish that SMS1 is essential for normal inner ear function. Sphingomyelin (SM) is a sphingolipid reported to function as a structural component of plasma membranes and to participate in signal transduction. The role of SM metabolism in the process of hearing remains controversial. Here, we examined the role of SM synthase (SMS), which is subcategorized into the family members SMS1 and SMS2, in auditory function. Measurements of auditory brainstem response (ABR) revealed hearing impairment in SMS1−/− mice in a low frequency range (4–16 kHz). As a possible mechanism of this impairment, we found that the stria vascularis (SV) in these mice exhibited atrophy and disorganized marginal cells. Consequently, SMS1−/− mice exhibited significantly smaller endocochlear potentials (EPs). As a possible mechanism for EP reduction, we found altered expression patterns and a reduced level of KCNQ1 channel protein in the SV of SMS1−/− mice. These mice also exhibited reduced levels of distortion product otoacoustic emissions. Quantitative comparison of the SV atrophy, KCNQ1 expression, and outer hair cell density at the cochlear apical and basal turns revealed no location dependence, but more macrophage invasion into the SV was observed in the apical region than the basal region, suggesting a role of cochlear location‐dependent oxidative stress in producing the frequency dependence of hearing loss in SMS1−/− mice. Elevated ABR thresholds, decreased EPs, and abnormal KCNQ1 expression patterns in SMS1−/− mice were all found to be progressive with age. Mice lacking SMS2, however, exhibited neither detectable hearing loss nor changes in their EPs. Taken together, our results suggest that hearing impairments occur in SMS1−/− but not SMS2−/− mice. Defects in the SV with subsequent reductions in EPs together with hair cell dysfunction may account, at least partially, for h