Molecular pathology of deafness due to mutation in PMP22

描述(申请人提供)：遗传物质对耳聋总负担的30%-50%负有责任。阐明与耳聋有关的基因产物及其表达模式，将有助于剖析耳聋和正常听力背后的分子事件。在一个进行性和深度耳聋与Charcot-Marie-Tooth病(CMT；和遗传性周围神经病)相关的大家族中，PMP22基因的一个独特突变被确定为临床表现的原因。PMP22基因编码的蛋白质(外周髓鞘蛋白)是神经系统的一个组成部分。PMP22蛋白的生物学功能尚不完全清楚，但它对神经轴突的适当髓鞘形成是必要的。髓鞘作为通过神经细胞传递的电信号的绝缘体，被认为是髓鞘形成异常导致CMT症状。PMP22在听力损失中的作用尚不清楚，尽管有趣的是PMP22的表达局限于神经和非神经组织，受CMT和耳聋影响的个体表现出神经和耳蜗组分对听力损失的影响。 PMP22是生长停滞特异性(Gas)基因家族的一员，已被证明调节基因表达、细胞死亡和细胞分裂。在非神经组织中，PMP22基因因其在细胞生长停滞和终末分化时特有的表达模式而在细胞分化和组织发育中发挥作用。因此，PMP22的表达被认为具有两个功能：在周围神经髓鞘形成中的作用和在非神经组织中调节细胞生长的作用。推测PMP22类似的双重表达是正常听力所必需的。 这项研究建议以颤抖者-J小鼠为模型，剖析与PMP22突变相关的耳聋的分子病理学。颤抖者-J小鼠携带PMP22基因的点突变，当表达在杂合状态时，表现出伴有听力障碍的神经病理表型。本研究对正常小鼠和突变PMP22小鼠耳蜗管中PMP22基因和蛋白的表达模式进行了比较研究。通过这项检查，将根据表达PMP22的细胞和耳蜗结构的类型来确定PMP22在听力发育中的潜在作用。此外，还将检查正常和突变小鼠的整体基因表达模式，以确定与PMP22功能水平相关的差异表达基因。通过对对照组和实验组的比较分析，确定基因表达谱的差异，有助于全面了解PMP22的功能及其与其他基因和基因产物的相互作用，并具体阐明其对内耳发育和功能的影响。

DESCRIPTION (provided by applicant): Genetic entities are responsible for 30-50% of the total burden of deafness. The elucidation of gene products responsible for deafness, and their expression patterns, will help dissect the molecular events underlying both deafness and normal hearing. In a large family with progressive and profound deafness associated with Charcot-Marie-Tooth disease (CMT; and inherited peripheral neuropathy), a unique mutation in the PMP22 gene was determined responsible for the clinical presentation. The protein encoded by the PMP22 gene (peripheral myelin protein) is a component of the nervous system. The biological function of the PMP22 protein is not completely understood, but it is necessary for the proper myelination of nerve axons. The myelin sheath acts as an insulator of the electrical signal that is transmitted through nerve cells, and it is thought that abnormal myelin formation results in the symptoms of CMT. The role of PMP22 in hearing loss remains unclear, although it is interesting that PMP22 expression has been localized to neural and non-neural tissues and individuals affected by CMT and deafness exhibit both neural and cochlear components to hearing loss. PMP22 is a member of the family of Growth arrest specific (Gas) genes, which have been shown to regulate gene expression, cell death and cell division. It has been speculated that in non-neural tissue the PMP22 gene plays a role in cell differentiation and tissue development because of its characteristic expression pattern at times of cellular growth arrest and terminal differentiation. Thus PMP22 expression has been proposed to have two functions: a role in peripheral nerve myelination and a role in cell growth regulation in non-neural tissues. It is hypothesized that a similar dual expression of PMP22 is necessary for normal hearing. This study proposes to dissect the molecular pathology of deafness associated with PMP22 mutations using the Trembler-J mouse as a model. The Trembler-J mouse carries a point mutation in the PMP22 gene that, when expressed in the heterozygous state, exhibits a neuropathic phenotype with auditory dysfunction. This study proposes a comparative evaluation of expression patterns of the murine PMP22 gene and protein in the cochlear duct for both normal mice and mice with a mutant PMP22. Through this examination a potential role of PMP22 in hearing development will by formulated based on the types of cells and cochlear structures that express PMP22. In addition, overall gene expression patterns will be examined in normal and mutant mice to identify genes differentially expressed relative to functional levels of PMP22. Determining the differences in gene expression profiles through comparative analysis of control and experimental groups should contribute to the general understanding of PMP22 function and its interactions with other genes and gene products, and specifically shed light on its influence of inner ear development and function.