Mice deficient in H+-ATPase a4 subunit have severe hearing impairment associated with enlarged endolymphatic compartments within the inner ear.
Mutations in the ATP6V0A4 gene lead to autosomal recessive distal renal tubular acidosis in patients, who often show sensorineural hearing impairment. A first Atp6v0a4 knockout mouse model that recapitulates the loss of H(+)-ATPase function seen in humans has been generated and recently reported (Norgett et al., 2012). Here, we present the first detailed analysis of the structure and function of the auditory system in Atp6v0a4(-/-) knockout mice. Measurements of the auditory brainstem response (ABR) showed significantly elevated thresholds in homozygous mutant mice, which indicate severe hearing impairment. Heterozygote thresholds were normal. Analysis of paint-filled inner ears and sections from E16.5 embryos revealed a marked expansion of cochlear and endolymphatic ducts in Atp6v0a4(-/-) mice. A regulatory link between Atp6v0a4, Foxi1 and Pds has been reported and we found that the endolymphatic sac of Atp6v0a4(-/-) mice expresses both Foxi1 and Pds, which suggests a downstream position of Atp6v0a4. These mutants also showed a lack of endocochlear potential, suggesting a functional defect of the stria vascularis on the lateral wall of the cochlear duct. However, the main K(+) channels involved in the generation of endocochlear potential, Kcnj10 and Kcnq1, are strongly expressed in Atp6v0a4(-/-) mice. Our results lead to a better understanding of the role of this proton pump in hearing function.
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
Beatriz
B
Lorente-Cánovas
Neil
N
Ingham
Elizabeth E
EE
Norgett
Zoe J
ZJ
Golder
Fiona E
FE
Karet Frankl
Karen P
KP
Steel
D000818:Animals; D000831:Animals, Newborn; D027321:Anion Transport Proteins / Q000378:metabolism; D007758:Ear, Inner / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D004710:Endolymph / Q000201:enzymology*; D004712:Endolymphatic Sac / Q000473:pathology / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005072:Evoked Potentials, Auditory; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D034381:Hearing Loss / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D021122:Protein Subunits / Q000172:deficiency* / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000172:deficiency* / Q000378:metabolism; D013316:Stria Vascularis / Q000378:metabolism / Q000473:pathology; D000076988:Sulfate Transporters; D025262:Vacuolar Proton-Translocating ATPases; D000098854:Kcnj10 Channel
D027321:Anion Transport Proteins; D051858:Forkhead Transcription Factors; C508689:Foxi1 protein, mouse; D051657:KCNQ1 Potassium Channel; D000098854:Kcnj10 Channel; C496910:Kcnq1 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; C490179:Atp6v0a4 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases