AUDITORY NEUROGENETICS

听力损失是人类最常见的感觉缺陷。在美国，大约每1000名新生儿中就有7名发生先天性、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，大约有一半被怀疑是遗传因素造成的。小鼠拥有强大的分子和基因技术，再加上小鼠和人类听力功能的相似性，使小鼠成为研究人类耳聋的有用模型系统。最近，我们发现在Deafwaddler(DFW)小鼠突变株的两个等位基因中，质膜钙ATPase 2基因(Pmca2)都发生了改变。我们还发现，PMCA2(该蛋白)高度集中在小鼠外毛细胞的静毛和内毛细胞的基侧膜中。这些数据，以及来自其他实验室的电生理学研究表明，PMCA2可以清除毛细胞中的钙，从而使立体纤毛能够传递听觉信息。在这里，我们建议：分析PMCA2在听觉和前庭系统中的表达，检测PMCA2表达的发育变化，寻找与Deafwaddler相互作用的新基因，并为鉴定具有类似Deafwaddler的突变的人类家族，开发人类PMCA2基因的遗传标记。我们还开发了小鼠7号染色体上颤动基因的高分辨率遗传和物理图谱。颤动基因的突变会导致听觉脑干中耳蜗核水平的过度活动和耳聋。我们建议克隆抖动相关基因，并分析抖动基因产物在小鼠体内的表达和功能。因为存在7个独立的抖动等位基因，我们应该能够将抖动基因突变的预测严重程度与观察到的不同抖动品系的表型严重程度的差异联系起来。我们对聋人和颤抖突变体的研究将分别识别对毛细胞的正常功能和听觉信息的正常传输至关重要的基因。除了简单地识别基因之外，小鼠还提供了额外的优势，即我们可以使用电生理、发育和遗传技术来更充分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.