ROLE OF EGR2 MUTATIONS IN PERIPHERAL MYELINOPATHIES

描述（来自申请人的摘要）：遗传性神经病是 最常见的人类遗传疾病。这些综合征的特点是 继发于神经髓鞘形成异常的严重运动和感觉缺陷 导致显著的患者发病率和死亡率。底层 这些神经病的遗传缺陷主要发生在编码 髓鞘结构蛋白MPZ、PMP-22和连接蛋白-32。然而最近， 转录因子Egr 2的突变也与这些相关。 综合征Egr 2和这些综合征之间的联系是在 Egr 2缺陷小鼠的外周神经似乎髓鞘化不良， 雪旺氏细胞分化停滞在早髓鞘阶段。在一起， 这些结果有力地表明，Egr 2是一个重要的调节因子， 分化程序，最终在髓鞘形成的许旺细胞中 表型。在这份提案中，我们概述了旨在了解 Egr 2调节髓鞘形成过程的分子机制。 使用腺病毒感染雪旺细胞的功能获得实验将 用于通过微阵列筛选进行Egr 2靶基因谱分析。 与遗传性神经病相关的egr 2突变体将在 体外髓鞘形成测定并测试它们激活表达的能力 Egr 2靶基因此外，神经病相关的Egr 2 突变位于与Nab蛋白相互作用的结构域中， Egr 2活性的调节剂。因此，我们将调查纳布的作用 调节髓鞘形成的蛋白质。在Nabl中存在突变或 将在遗传性神经病患者中寻找Nab 2基因。最后，吉恩 靶向将用于产生携带神经病相关Egr 2的小鼠， 突变，以创建这些遗传性神经病的小鼠模型。的 将检查这些小鼠的外周神经系统的缺陷， 雪旺细胞分化与周围神经髓鞘形成。表达 将在这些突变小鼠的神经中检测Egr 2调节基因的表达。这些 研究将为Egr 2突变如何导致外周血管疾病提供新的见解。 神经病变，可能导致这些疾病的新疗法的信息。

DESCRIPTION (From the Applicant's Abstract): Inherited neuropathies are among the most common human genetic diseases. These syndromes are characterized by severe motor and sensory deficits secondary to abnormal nerve myelination resulting in significant patient morbidity and mortality. The underlying genetic defects of these neuropathies occur primarily in genes encoding the myelin structural proteins MPZ, PMP-22 and connexin-32. Recently, however, mutations in the transcription factor Egr2 have also been associated with these syndromes. The connection between Egr2 and these syndromes was made after peripheral nerves in Egr2-deficient mice appeared poorly myelinated due to a Schwann cell differentiation arrest at the promyelinating stage. Together, these results strongly suggest that Egr2 is a crucial regulator of a differentiation program, which culminates in the myelinating Schwann cell phenotype. In this proposal, we outline experiments aimed at understanding the molecular mechanisms by which Egr2 regulates the myelination process. Gain-of-function experiments using adenovirus infection of Schwann cells will be utilized to perform Egr2 target gene profiling via microarray screening. Egr2 mutants associated with inherited neuropathies will be characterized in in vitro myelination assays and tested for their ability to activate expression of Egr2 target genes. In addition, one of the neuropathy-associated Egr2 mutations is located in the domain that interacts with the Nab proteins, modulators of Egr2 activity. We will therefore investigate the role of the Nab proteins in regulating myelination. The presence of mutations in the Nabl or Nab2 genes will be sought in patients with inherited neuropathy. Finally, gene targeting will be used to produce mice that harbor neuropathy-associated Egr2 mutations in order to create mouse models of these inherited neuropathies. The peripheral nervous system of these mice will be examined for deficits in Schwann cell differentiation and peripheral nerve myelination. The expression of Egr2-regulated genes will be examined in nerves of these mutant mice. These studies will provide new insight into how mutations in Egr2 lead to peripheral neuropathies, information that may lead to novel therapies for these diseases.