Hearing loss is the most frequent sensory defect in humans. Congenital, perinatal or early onset hearing loss occurs in approximately 7 out of 1000 neonates in the United States. In approximately half of the children born with severe hearing impairment, a genetic contribution is suspected. The powerful molecular and genetic techniques available in mouse combined with the functional similarities between mouse and human audition make mouse a useful model system for studying human deafness. Recently, we have shown that the plasma membrane calcium ATPase type 2 gene (Pmca2) is altered in both alleles of the deafwaddler (dfw) mouse mutant strain. We have also shown that PMCA2 (the protein) is highly concentrated in stereocilia of mouse outer hair cells and in the basolateral membrane of inner hair cells. These data, along with electrophysiological studies from other labs, suggest that PMCA2 clears calcium from hair cells, thereby allowing stereocilia to transduce auditory information. Here we propose: to analyze PMCA2 expression in the auditory and vestibular systems, to examine developmental changes in PMCA2 expression, to identify new genes that interact with deafwaddler, and, toward identifying human families with mutations analogous to deafwaddler, to develop genetic markers for the human PMCA2 gene. We have also developed high resolution genetic and physical maps for the quivering locus on mouse chromosome 7. Mutations in the quivering gene cause hyperactivity as well as deafness that arises at the level of the cochlear nucleus in the auditory brainstem. We propose to clone the gene underlying quivering and to analyze the expression and function of the quivering gene product in mice. Because seven independent alleles of quivering exist, we should be able to correlate the predicted severity of mutations in the quivering gene with the observed differences in severity in the phenotypes in different strains of quivering. Our studies on the deafwaddler and quivering mutants will identify genes critical to normal functioning of hair cells and to normal transmission of auditory information, respectively. Beyond simply identifying the gene, mice provide the additional advantage that we can use electrophysiological, developmental, and genetic techniques to more fully understand the biological role of these genes in auditory function.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Special Emphasis Panel (ZRG1-IFCN-6 (03))
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Freeman, Nancy
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University of Washington
Schools of Medicine
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Minich, Rebecca R; Li, Jin; Tempel, Bruce L (2017) Early growth response protein 1 regulates promoter activity of ?-plasma membrane calcium ATPase 2, a major calcium pump in the brain and auditory system. BMC Mol Biol 18:14
Peguero, Braulio; Tempel, Bruce L (2015) A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice. J Assoc Res Otolaryngol 16:459-71
Kopp-Scheinpflug, Conny; Tempel, Bruce L (2015) Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder. Hear Res 330:213-20
Wang, Yuan; Sakano, Hitomi; Beebe, Karisa et al. (2014) Intense and specialized dendritic localization of the fragile X mental retardation protein in binaural brainstem neurons: a comparative study in the alligator, chicken, gerbil, and human. J Comp Neurol 522:2107-28
Watson, Claire J; Lies, Sarah M; Minich, Rebecca R et al. (2014) Changes in cochlear PMCA2 expression correlate with the maturation of auditory sensitivity. J Assoc Res Otolaryngol 15:543-54
Street, Valerie A; Kujawa, Sharon G; Manichaikul, Ani et al. (2014) Resistance to noise-induced hearing loss in 129S6 and MOLF mice: identification of independent, overlapping, and interacting chromosomal regions. J Assoc Res Otolaryngol 15:721-38
Watson, Claire J; Tempel, Bruce L (2013) A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers. Hear Res 304:41-8
McBride, Ethan G; Rubel, Edwin W; Wang, Yuan (2013) Afferent regulation of chicken auditory brainstem neurons: rapid changes in phosphorylation of elongation factor 2. J Comp Neurol 521:1165-83
Wang, Wenying; Kim, Hyo Jeong; Lv, Ping et al. (2013) Association of the Kv1 family of K+ channels and their functional blueprint in the properties of auditory neurons as revealed by genetic and functional analyses. J Neurophysiol 110:1751-64
Robbins, Carol A; Tempel, Bruce L (2012) Kv1.1 and Kv1.2: similar channels, different seizure models. Epilepsia 53 Suppl 1:134-41

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