Molecular pathology of deafness due to mutation in PMP22

描述（由申请人提供）：遗传实体占耳聋总负担的30-50%。对耳聋基因产物及其表达模式的阐明，将有助于剖析耳聋和正常听力的分子基础。在一个进行性和深度耳聋与腓骨肌萎缩症（CMT;和遗传性周围神经病变），一个独特的突变在PMP 22基因被确定负责的临床表现的大家庭。由PMP 22基因编码的蛋白质（外周髓鞘蛋白）是神经系统的组成部分。PMP 22蛋白的生物学功能尚未完全了解，但它对于神经轴突的适当髓鞘形成是必需的。髓鞘充当通过神经细胞传输的电信号的绝缘体，并且认为异常髓鞘形成导致CMT的症状。PMP 22在听力损失中的作用仍不清楚，尽管有趣的是，PMP 22表达已定位于神经和非神经组织，并且受CMT和耳聋影响的个体表现出听力损失的神经和耳蜗成分。 PMP 22是生长停滞特异性（Gas）基因家族的成员，其已被证明调节基因表达、细胞死亡和细胞分裂。据推测，在非神经组织中，由于其在细胞生长停滞和终末分化时的特征性表达模式，PMP 22基因在细胞分化和组织发育中起作用。因此，已经提出PMP 22表达具有两种功能：在外周神经髓鞘形成中的作用和在非神经组织中的细胞生长调节中的作用。据推测，一个类似的双重表达的PMP 22是必要的正常听力。 本研究拟以Trembler-J小鼠为模型，探讨与PMP 22突变相关的耳聋的分子病理学。Trembler-J小鼠在PMP 22基因中携带点突变，当以杂合状态表达时，表现出具有听觉功能障碍的神经病表型。本研究提出了一个比较评估的表达模式的小鼠PMP 22基因和蛋白质在耳蜗管正常小鼠和小鼠与突变的PMP 22。通过这项研究，将根据表达PMP 22的细胞类型和耳蜗结构来阐述PMP 22在听力发育中的潜在作用。此外，将在正常和突变小鼠中检查总体基因表达模式，以鉴定相对于PMP 22功能水平差异表达的基因。通过对照组和实验组的比较分析确定基因表达谱的差异，应有助于对PMP 22功能及其与其他基因和基因产物的相互作用的一般理解，并特别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.