Endocochlear potential depends on Cl− channels: mechanism underlying deafness in Bartter syndrome IV

• DOI: 10.1038/emboj.2008.203
• Publication Date: 2008-10-02T12:06:54Z
• Authors: Gesa Rickheit; Hannes Maier; Nicola Strenzke; Corina E Andreescu; Chris I De Zeeuw; Adrian Muenscher; Anselm A Zdebik; Thomas J Jentsch
• Keywords: mice; Deafness; Models, Biological; Chloride Channels/metabolism; Evoked Potentials/physiology; Hair Cells, Auditory/metabolism; Endolymph; Mice; 03 medical and health sciences; Chloride Channels; Hair Cells, Auditory; Stria Vascularis/pathology; Animals; Humans; Transcription Factors/metabolism; Evoked Potentials; Mice, Knockout; 0303 health sciences; DNA-Binding Proteins/metabolism; endolymph; Integrases; SOXE Transcription Factors; High Mobility Group Proteins; Sox10 ; Inner Ear ; Otoacoustic Emission ; Anion Transport ; Potassium Recycling; Bartter Syndrome; Membrane Proteins; Stria Vascularis; High Mobility Group Proteins/metabolism; Cochlea; DNA-Binding Proteins; Mice, Inbred C57BL; Deafness/complications; Cochlea/metabolism; Membrane Proteins/metabolism; Vestibule, Labyrinth/metabolism; Bartter Syndrome/complications; Gene Deletion; Integrases/metabolism

Human Bartter syndrome IV is an autosomal recessive disorder characterized by congenital deafness and severe renal salt and fluid loss. It is caused by mutations in BSND, which encodes barttin, a beta-subunit of ClC-Ka and ClC-Kb chloride channels. Inner-ear-specific disruption of Bsnd in mice now reveals that the positive potential, but not the high potassium concentration, of the scala media depends on the presence of these channels in the epithelium of the stria vascularis. The reduced driving force for K(+)-entry through mechanosensitive channels into sensory hair cells entails a profound congenital hearing loss and subtle vestibular symptoms. Although retaining all cell types and intact tight junctions, the thickness of the stria is reduced early on. Cochlear outer hair cells degenerate over several months. A collapse of endolymphatic space was seen when mice had additionally renal salt and fluid loss due to partial barttin deletion in the kidney. Bsnd(-/-) mice thus demonstrate a novel function of Cl(-) channels in generating the endocochlear potential and reveal the mechanism leading to deafness in human Bartter syndrome IV.