Genetic Etiologies of Horizontal Strabismus

水平斜视的遗传病因学

• 批准号: 6729780
• 负责人: Elizabeth C. Engle
• 金额: $ 39.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729780
• 关键词: clinical research; congenital eye disorder; cranial nerves; disease /disorder etiology; eye coordination disorder; eye movement disorders; family genetics; functional /structural genomics; gene mutation; genetic mapping; genetic screening; genetic susceptibility; human subject; interneurons; laboratory mouse; molecular cloning; motor neurons; neuropathology; oculomotor nerve; oculomotor nuclei; patient oriented research; protein structure function; scoliosis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：为了深入了解动眼疾病和斜视的发病机制，我们正在研究被称为“先天性颅骨神经支配障碍”（CCDD）的先天性眼球运动障碍的遗传基础，并研究这些遗传缺陷如何扰乱发育动眼神经下运动神经元系统。 Duane 综合征和 CFEOM1 的神经病理学发现以及 CFEOM2 基因 PHOX2A (ARIX) 在中脑发育中的作用支持以下假设：这些疾病是由于运动神经元异常发育或脑神经轴突靶向继发性眼外肌神经支配所致。 我们认为，CFEOM 和上睑下垂是由动眼神经和滑车核和神经发育不良引起的，杜安综合征（DS）是由外展运动神经元发育不良引起的，水平凝视麻痹（HGP）是由外展运动神经元和中间神经元发育不良引起的。 我们定义了 5 个 CCDD 基因位点，并将 PHOX2A 和 SALL4 分别鉴定为 CFEOM2 和 Duane 放射线综合征中的突变基因。 我们正在对剩余的 CFEOM 基因进行定位克隆。 在这笔赠款中，我们寻求资金来识别杜安综合征中的两个突变基因（DURS1 和 DURS2）以及进行性脊柱侧凸水平凝视麻痹（HGPPS）中的一个突变基因。 通过识别这些导致复杂水平斜视的基因，我们将定义这些疾病的遗传基础，开发一种工具来研究其分子病因，并获得对动眼疾病以及外展核和神经发育的发病机制的重要见解。 我们将通过 (1) 识别 HGPPS 疾病基因并分析家系中的致病突变来实现这些目标。 (2) 鉴定DURS2疾病基因并分析家系中的致病突变。 (3) 定义新的 DURS1 细胞遗传学断点并确定候选 DURS1 基因的突变是否会导致 DS。 (4) 确定已识别的 DS 和 HGPPS 基因的突变是否会导致散发性 DS 和/或更常见形式的水平斜视。 (5) 启动水平CCDD基因及其蛋白质产物的结构和功能表征。