title: A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers.
abstract: 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.
authors.affiliation: The Virginia Merrill Bloedel Hearing Research Center, Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195, USA.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Watson
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Tempel
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics* / Q000502:physiology*; D020013:Calcium Signaling; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D006198:Hair Cells, Auditory / Q000502:physiology; D006309:Hearing / Q000235:genetics* / Q000502:physiology*; D034381:Hearing Loss / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009154:Mutation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D059547:Stereocilia / Q000502:physiology
chemical_list: D015820:Cadherins; C499091:Cdh23 protein, mouse; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse
keywords: ABR; ANOVA; Ca(2+); ENU; HET; IHC; JAX; Jackson Laboratory; MET; MFE; MUT; N-ethyl-N-nitrosourea; OHC; PMCA; SEM; SNP; SPL; WT; age-related hearing loss; ahl; analysis of variance; auditory-evoked brainstem response; calcium; dB; deafwaddler; decibels; dfw; heterozygote; inner hair cell; mechanoelectric transducer; minimum free energy; mutant; outer hair cell; plasma membrane calcium ATPase; single-nucleotide polymorphism; sound pressure level; standard error of the mean; wild-type