ATP6V1C1 deficiency impairs auditory and vestibular hair cell function and leads to sensorineural hearing loss in humans and mice.

Multiple genes encoding v-ATPase subunits are associated with various forms of syndromic hearing loss. Their functions in hair cells, the key sensory cells required for hearing and balance, remain unclear. In this study, linkage analysis and exome sequencing of a large autosomal dominant family with non-syndromic deafness identify a pathogenic p.R281P variant in ATP6V1C1 that encodes the C1 subunit of the v-ATPase. Conditional knock-out (CKO) of Atp6v1c1 in mouse hair cells results in early-onset sensorineural hearing loss and vestibular malfunction. The CKO mice show synaptic defects in inner hair cells, evidenced by decreased wave I amplitude and prolonged latency of the auditory brainstem responses, loss of inner hair cell ribbon synapses, accumulation of endocytic compartments, and absence of F-actin mesh network surrounding the active zones. The cochlear and vestibular hair cells of the CKO mice also undergo disrupted autophagic flux and apoptosis. The Atp6v1c1 p.R281P knock-in mice develop late-onset, high-frequency hearing loss with normal hair cell morphology but degenerated spiral ganglion neurons due to disrupted autophagic flux and apoptosis. Our study reveals ATP6V1C1 as a causative gene for non-syndromic deafness and its important roles in maintenance and synaptic function of hair cells.