Genetic and anatomic basis of the fibrosis syndromes

描述(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，每种紊乱在球体的固定位置上都不同 以及特定受累的脑神经(S)和眼外肌 (EOMS)。两种纤维化综合征的神经病理基础是 Duane综合征是由于缺乏外展神经和 核，而CFEOM1是由于没有上位分裂的结果 动眼神经和相应的动眼神经亚核。实验室的 长期目标是揭示纤维化综合征的分子基础。 并研究动眼下运动神经元系统的发育。 为了实现这些目标，我们从基因上定义了四个先天性纤维化基因 和一个先天性上睑下垂基因，正在进行定位克隆 这些基因。在这笔赠款中，我们寻求资金以解决以下具体问题 目的：(1)鉴定先天纤维化综合征家系 临床和遗传学研究，并分析他们的DNA是否与已知的 CFEOM基因座。(2)明确CFEOM的解剖学基础和功能基础 遗传性视网膜瘤患者的高分辨率眼眶MRI研究 家人。(3)克隆CFEOM1病基因(突变最多的基因 先天性纤维化综合征常见遗传型)及CFEOM1分析 致病基因突变的家庭。(四)启动结构性和功能性 CFEOM1 RNA和蛋白质产物的鉴定。意义： 斜视障碍的分子基础仍然知之甚少。虽然很罕见， 一些纤维化综合征是遗传的，因此提供了一种独特的 有机会调查这类斜视障碍的病因学。 我们大量的CFEOM1系列，加上详细的物理地图 和获得CFEOM1关键区域内的基因组序列，将我们置于 一个独特的位置来鉴定这种疾病的基因。此外，这种关联性 这些遗传数据与拟议的临床、解剖和功能 基因定义的患者的特征提供了独特和强大的 为表型-基因型相关性和功能研究奠定基础。通过 定义CFEOM1的遗传学和解剖学基础，我们将开发一个工具 以研究其分子基础并寻找相关的纤维化基因， 有了它，我们应该对脑干颅脑有重要的新见解 神经发育。这些数据将对我们理解 这些基因的发育作用，也应该有助于改进 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.