AUDITORY NEUROGENETICS

听力损失是人类最常见的感觉缺陷。在美国，每1000名新生儿中约有7名患有先天性、围产期或早发性听力损失。 在出生时患有严重听力障碍的儿童中，约有一半怀疑是遗传因素造成的。 小鼠强大的分子和遗传学技术结合小鼠与人类听觉功能的相似性，使小鼠成为研究人类耳聋的有用模型系统。最近，我们已经表明，质膜钙ATP酶2型基因（Pmca2）改变的两个等位基因的swaddler（dfw）小鼠突变株。 我们还表明，PMCA 2（蛋白质）高度集中在小鼠外毛细胞的静纤毛和内毛细胞的基底外侧膜。这些数据，沿着来自其他实验室的电生理学研究，表明PMCA 2清除毛细胞中的钙，从而使静纤毛吸收听觉信息。 在此，我们建议：分析PMCA 2在听觉和前庭系统中的表达，检查PMCA 2表达的发育变化，鉴定与Escherichwaddler相互作用的新基因，以及鉴定具有类似Escherichwaddler突变的人类家族，开发人类PMCA 2基因的遗传标记。我们还开发了小鼠7号染色体上的E1基因座的高分辨率遗传和物理图谱。 在听觉脑干的耳蜗核水平上，E2基因的突变会引起多动症和耳聋。 我们建议克隆的基因潜在的ESTA和分析ESTA基因产物在小鼠中的表达和功能。 由于存在7个独立的等位基因，我们应该能够将预测的突变严重性与观察到的不同菌株的表型严重性差异相关联。我们的研究，对pneumwaddler和pneumoniae突变体将确定基因的正常功能的毛细胞和听觉信息的正常传输，分别至关重要。除了简单地识别基因，小鼠提供了额外的优势，我们可以使用电生理学，发育和遗传技术来更全面地了解这些基因在听觉功能中的生物学作用。

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.