Genetic Etiologies of Horizontal Strabismus

描述（由申请人提供）：为了深入了解动眼病和斜视的发病机制，我们正在研究先天性眼动障碍（即先天性颅神经支配障碍）的遗传基础，并研究这些遗传缺陷如何干扰动眼病下运动神经元系统的发育。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了这些疾病是由运动神经元异常发育或继发性眼外肌神经支配障碍引起的脑神经轴突靶向引起的假设。我们认为CFEOM和上睑下垂是由眼动核和滑车核和神经发育不良引起的，Duane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。我们确定了5个CCDD基因位点，并确定PHOX2A和SALL4分别是CFEOM2和Duane放射状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，我们寻求资金来鉴定Duane综合征中的两个突变基因（DURS1和DURS2）和水平凝视性麻痹伴进行性脊柱侧凸（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，开发一种研究其分子病因的工具，并对动眼病和外展核和神经发育的发病机制获得重要的见解。我们将通过(1)确定HGPPS疾病基因和分析致病突变的家系来实现这些目标。(2)鉴定DURS2疾病基因，分析致病突变家系。(3)确定新的DURS1细胞遗传学断点，并确定候选DURS1基因突变是否会导致DS。(4)确定已鉴定的DS和HGPPS基因突变是否会导致散发性DS和/或更常见的水平斜视。(5)启动水平CCDD基因及其蛋白产物的结构和功能表征。

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.