An absent WD domain in the autophagy protein ATG16L1 leads to auditory and vestibular dysfunction and otoconial deficits in mice

Objectives: To examine the inner ear functions of mice that lack the WD domain (δWD) of autophagy protein ATG16L1. Design: Mice were assessed with vestibular evoked potentials (VsEPs), auditory brainstem responses (ABRs) and four δWD mice were observed with electron microscopy to assess otolith otoconia loss, and cochlear hair cell loss. Study sample: Seven δWD mice and four control mice. Results: Compared to control mice, VsEP thresholds were elevated, latencies increased and amplitudes decreased in the δWD mice. ABR thresholds were elevated for the 32 kHz tonebursts (but not 8 or 16 kHz) in the δWD mice compared to controls. Electron microscopy in four δWD mice revealed a complete absence of otoconia in three of four otolith organs, with the remaining mouse (perhaps a failed mutant mouse, due to incomplete penetrance of this phenotype) showing a normal complement of otoconia. In the cochlea, abnormal hair cells were observed, typically showing modest hair cell loss or damage of hair cells or stereocilia. Conclusions: Three confirmed δWD mice showed missing otoconia, and changes in VsEPs and ABRs suggest that non-canonical autophagy pathways involved in endomembrane repair and removal are important for maintaining vestibular (and perhaps auditory) function in the inner ear.