Genetic Etiologies of Horizontal Strabismus

为了深入了解眼病和斜视的发病机制，我们正在研究 先天性眼球运动障碍的遗传学基础 研究这些遗传缺陷是如何干扰下眼神经发育的 运动神经元系统Duane综合征和CFEOM 1的神经病理学表现及其在神经系统损害中的作用 CFEOM 2基因PHOX 2A（ARIX）在中脑发育中的作用支持了这些疾病 运动神经元的异常发育或颅神经的轴突靶向导致继发性 眼外肌神经支配障碍我们认为CFEOM和上睑下垂是由于 Duane综合征（DS）是由于眼神经和眼轮匝肌核和神经发育不良所致， 外展肌运动神经元和水平凝视麻痹（HGP）是外展肌发育不良的结果 运动神经元和中间神经元。我们已经确定了5个CCDD基因座，并确定了PHOX 2A和SALL 4 分别作为CFEOM 2和Duane放射线综合征中突变的基因。我们正在 定位克隆剩余的CFEOM基因。在这项拨款中，我们寻求资金，以确定两个基因 Duane综合征（DURS 1和DURS 2）中的基因突变和水平凝视麻痹中的基因突变 进行性脊柱侧凸（HGPPS）。通过识别这些导致复杂水平斜视的基因， 确定这些疾病的遗传基础，开发一种研究其分子病因的工具， 对眼病和外展神经核和神经的发病机制有重要的认识 发展我们将通过（1）鉴定HGPPS疾病基因并分析 致病突变的系谱。(2)确定DURS 2疾病基因并分析家系 致病突变的基因(3)定义新的DURS 1细胞遗传学断点并确定 候选DURS 1基因的突变导致DS。(4)确定已鉴别DS中的突变， HGPPS基因引起散发性DS和/或更常见形式的水平斜视。（5）发起 水平CCDD基因及其蛋白产物的结构和功能表征。

To gain insight into the pathogenesis of oculomotor disease and strabismus, we are investigating the genetic basis of congenital eye movement disorders referred to as 'congenital cranial dysinnervation disorders' (CCDDs) and studying how these genetic defects perturb development of the oculomotor lower motor neuron system. The neuropathologic findings in Duane syndrome and CFEOM1 and the role of the CFEOM2 gene, PHOX2A (ARIX), in midbrain development support the hypothesis that these disorders result from aberrant development of motor neurons or axonal targeting of cranial nerves with secondary extraocular muscle dysinnervation. We propose that CFEOM and ptosis result from maldevelopment of oculomotor and trochlear nuclei and nerves, Duane syndrome (DS) results from maldevelopment of abducens motoneurons, and horizontal gaze palsy (HGP) results from maldevelopment of abducens motoneurons and interneurons. We have defined five CCDD genetic loci and identified PHOX2A and SALL4 as the genes mutated in CFEOM2 and Duane radial ray syndrome, respectively. We are in the process of positionally cloning the remaining CFEOM genes. In this grant, we seek funding to identify two genes mutated in Duane syndrome (DURS1 and DURS2) and a gene mutated in horizontal gaze palsy with progressive scoliosis (HGPPS). By identifying these genes that cause complex horizontal strabismus we will define the genetic basis of these disorders, develop a tool with which to study their molecular etiologies, and gain important insight into the pathogenesis of oculomotor disease and abducens nuclear and nerve development. We will address these Aims by (1) Identifying the HGPPS disease gene and analyzing pedigrees for disease-causing mutations. (2) Identifying the DURS2 disease gene and analyzing pedigrees for disease-causing mutations. (3) Defining a new DURS1 cytogenetic breakpoint and determining if mutations in candidate DURS1 genes cause DS. (4) Determining if mutations in the identified DS and HGPPS genes cause sporadic DS and/or more common forms of horizontal strabismus. And (5) Initiating structural and functional characterization of the horizontal CCDD genes and their protein products.