Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV.
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.
Rickheit
Gesa
G
Leibniz-Institut für Molekulare Pharmakologie, Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
Maier
Hannes
H
Strenzke
Nicola
N
Andreescu
Corina E
CE
De Zeeuw
Chris I
CI
Muenscher
Adrian
A
Zdebik
Anselm A
AA
Jentsch
Thomas J
TJ
D000818:Animals; D001477:Bartter Syndrome / Q000150:complications* / Q000378:metabolism*; D018118:Chloride Channels / Q000378:metabolism*; D003051:Cochlea / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003638:Deafness / Q000150:complications* / Q000378:metabolism*; D004710:Endolymph; D005071:Evoked Potentials / Q000502:physiology*; D017353:Gene Deletion; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D055757:SOXE Transcription Factors; D013316:Stria Vascularis / Q000473:pathology / Q000648:ultrastructure; D014157:Transcription Factors / Q000378:metabolism; D014722:Vestibule, Labyrinth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
C486687:Bsnd protein, mouse; D018118:Chloride Channels; C489933:Clcnka protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008565:Membrane Proteins; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases