Genetic and anatomic basis of the fibrosis syndromes

描述（由申请人提供）：先天性纤维化综合征是 以限制性眼肌麻痹为特征的眼球运动障碍， 没有上睑下垂，每种疾病在眼球的固定位置上都不同 以及在特别受影响的颅神经和眼外肌中 （EOM）。两种纤维化综合征的神经病理学基础已被证实。 Duane综合征是由于外展神经缺失引起的， CFEOM 1是由于缺乏核的上级分裂， 眼神经和相应的眼神经亚核。实验室的 长期目标是揭示纤维化综合征的分子基础 研究眼下运动神经元系统的发育。 为了实现这些目标，我们在遗传学上定义了四个先天性纤维化位点， 和一个先天性上睑下垂位点，并正在进行定位克隆 这些基因。在这项赠款中，我们寻求资金，以解决以下具体问题 目的：（1）确定先天性纤维化综合征的家系， 临床和遗传研究，并分析其DNA与已知的 CFEOM基因座。(2)通过以下方式定义CFEOM的解剖和功能基础： 高分辨率眼眶MRI研究在受影响的成员遗传定义 家庭(3)克隆CFEOM 1疾病基因（该基因在大多数情况下是突变的）， 先天性纤维化综合征的常见遗传形式），并分析CFEOM 1 致病突变的家庭。(4)启动结构和功能 CFEOM 1 RNA和蛋白质产物的表征。Significance：The 斜视障碍的分子基础仍然知之甚少。虽然罕见， 几种纤维化综合征是遗传的，因此提供了独特的 有机会调查这一子集的斜视疾病的病因。 我们收集了大量CFEOM 1家族，以及详细的物理图谱 并获得CFEOM 1关键区域内的基因组序列， 一个独特的位置来识别这种疾病的基因。此外，相关性 这些基因数据与拟议的临床，解剖和功能 基因定义的患者的表征提供了一个独特的和强大的 表型-基因型相关性和功能研究的基础。通过 定义CFEOM 1的遗传和解剖基础，我们将开发一种工具， 研究其分子基础并寻找相关的纤维化基因， 我们应该借此获得对脑干颅 神经发育这些数据对我们了解 这些基因的发育作用，也应该有助于改善 纤维化综合征的治疗。

DESCRIPTION (provided by applicant): The congenital fibrosis syndromes are oculomotility disorders characterized by restrictive ophthalmoplegia with or without ptosis, and each disorder varies in the fixed position of the globes and in the specifically affected cranial nerve(s) and extraocular muscles (EOMs). The neuropathologic bases of two fibrosis syndromes have been described; Duane syndrome results from absence of the abducens nerve and nucleus, while CFEOM1 results from an absence of the superior division of the oculomotor nerve and corresponding oculomotor subnuclei. The laboratory's long-term goals are to uncover the molecular basis of the fibrosis syndromes and to study the development of the oculomotor lower motor neuron system. Toward these goals, we have genetically defined four congenital fibrosis loci and one congenital ptosis locus, and are in the process of positionally cloning these genes. In this grant, we seek funding to address the following specific aims: (1) Identify families with the congenital fibrosis syndromes for our clinical and genetic studies and analyze their DNA for linkage to the known CFEOM loci. (2) Define the anatomic and functional basis of CFEOM by high-resolution orbital MRI studies in affected members of genetically defined families. (3) Clone the CFEOM1 disease gene (which is mutated in the most common inherited form of the congenital fibrosis syndromes) and analyze CFEOM1 families for disease-causing mutations. (4) Initiate structural and functional characterization of the CFEOM1 RNA and protein product. Significance: The molecular bases of strabismic disorders remain poorly understood. Though rare, several of the fibrosis syndromes are inherited, and thus provide a unique opportunity to investigate the etiology of this subset of strabismic disorders. Our large collection of CFEOM1 families, coupled with a detailed physical map and access to genomic sequence within the CFEOM1 critical region, places us in a unique position to identify this disease gene. In addition, the correlation of this genetic data with the proposed clinical, anatomic, and functional characterization of genetically defined patients provides a unique and strong foundation for phenotype-genotype correlations and functional studies. By defining the genetic and anatomic bases of CFEOM1, we will develop a tool with which to study its molecular basis and to search for related fibrosis genes, and with which we should gain important new insights into brainstem cranial nerve development. These data will be invaluable to our understanding of the developmental roles of these genes, and should also contribute to improved therapy of the fibrosis syndromes.