Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Wolfram syndrome (WS) is a rare neurodegenerative disease encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) and neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, associated with a decrease of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase-β1 subunit, a key protein for the maintenance of the EP. Overall, our data support an important role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1-subunit.