A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers

Tight regulation of calcium (Ca2+) concentrations in the stereocilia bundles of auditory hair cells of the inner ear is critical to normal auditory transduction. The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereo...

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Bibliographic Details
Published in:Hearing research 2013-10, Vol.304, p.41-48
Main Authors: Watson, Claire J, Tempel, Bruce L
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Sequence
Animals
Base Sequence
Cadherins - genetics
Cadherins - physiology
Calcium Signaling
Evoked Potentials, Auditory, Brain Stem
Female
Hair Cells, Auditory - physiology
Hearing - genetics
Hearing - physiology
Hearing Loss - genetics
Hearing Loss - physiopathology
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Mutant Strains
Mutation
Plasma Membrane Calcium-Transporting ATPases - deficiency
Plasma Membrane Calcium-Transporting ATPases - genetics
Plasma Membrane Calcium-Transporting ATPases - physiology
Stereocilia - physiology
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Summary:Tight regulation of calcium (Ca2+) concentrations in the stereocilia bundles of auditory hair cells of the inner ear is critical to normal auditory transduction. The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca2+ in the endolymph. This study characterizes a novel null Atp2b2 allele, dfw(i5), by examining cochlear anatomy, vestibular function and auditory physiology in mutant mice. Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca2+ inside the stereocilia bundles. However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene. This study further resolves the interaction between Atp2b2 and Cdh23 in a gene dosage and frequency-dependent manner, and finds that low frequencies are significantly affected by the interaction. In +/dfw(i5) mice, one mutant copy of Cdh23 is sufficient to cause broad frequency hearing impairment. Additionally, we report another modifying interaction with Atp2b2 on auditory sensitivity, possibly caused by an unidentified hearing loss gene in mice.
ISSN:1878-5891
DOI:10.1016/j.heares.2013.06.003