Genetic Etiologies of Horizontal Strabismus

描述（由申请人提供）：为了深入了解眼病和斜视的发病机制，我们正在研究被称为“先天性颅神经支配障碍”（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干扰眼下运动神经元系统的发育。 Duane综合征和CFEOM 1的神经病理学结果以及CFEOM 2基因PHOX 2A（ARIX）在中脑发育中的作用支持了以下假设：这些疾病是由于运动神经元的异常发育或继发性眼外肌神经支配障碍的颅神经轴突靶向所致。 我们认为CFEOM和上睑下垂是由于眼神经和肌营养神经核和神经发育不良所致，Duane综合征（DS）是由于外展神经运动神经元发育不良所致，水平凝视麻痹（HGP）是由于外展神经运动神经元和中间神经元发育不良所致。 我们已经确定了5个CCDD基因位点，并确定PHOX 2A和SALL 4分别为CFEOM 2和Duane放射线综合征的突变基因。 我们正在定位克隆剩余的CFEOM基因。 在这项资助中，我们寻求资金来确定Duane综合征中的两个突变基因（DURS 1和DURS 2）和进行性脊柱侧凸水平凝视麻痹（HGPPS）中的一个突变基因。 通过识别这些基因，导致复杂的水平斜视，我们将定义这些疾病的遗传基础，开发一种工具，研究其分子病因，并获得重要的洞察眼病的发病机制和外展神经核和神经发育。 我们将通过（1）鉴定HGPPS疾病基因并分析致病突变的家系来实现这些目标。(2)鉴定DURS 2疾病基因并分析致病突变的家系。(3)定义新的DURS 1细胞遗传学断点，并确定候选DURS 1基因突变是否导致DS。 (4)确定所鉴定的DS和HGPPS基因中的突变是否引起散发性DS和/或更常见形式的水平斜视。 （5）对水平CCDD基因及其蛋白产物进行结构和功能鉴定。

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.