Origin of Vestibular Dysfunction in Usher Syndrome Type 1B

It is still debated to what extent the vestibular deficits in Usher patients are due to either central vestibulocerebellar or peripheral vestibular problems. Here, we determined the origin of the vestibular symptoms in Usher 1B patients by subjecting them to compensatory eye movement tests and by investigating the shaker-1 mouse model, which is known to have the same mutation in the myosin-VIIa gene as Usher 1B patients. We show that myosin-VIIa is not expressed in the human or mouse cerebellum and that the vestibulocerebellum of both Usher 1B patients and shaker-1 mice is functionally intact in that the gain and phase values of their optokinetic reflex are normal. In addition, Usher 1B patients and shaker-1 mice do not show an angular vestibuloocular reflex even though eye movement responses evoked by electrical stimulation of the vestibular nerve appear intact. Finally, we show histological abnormalities in the vestibular hair cells of shaker-1 mice at the ultrastructural level, while the distribution of the primary vestibular afferents and the vestibular brainstem circuitries are unaffected. We conclude that the vestibular dysfunction of Usher 1B patients and shaker-1 mice is peripheral in origin.