Functional study of a novel gene involved in human retinal disease

描述(申请人提供)：该项目的长期目标是确定人类Leber先天性巨结肠(LCA)相关基因的分子功能。LCA最初是由Theodor Leber在大约150年前描述为一种“宫内”形式的视网膜色素变性。现在，LCA仍然是导致失明的重要原因，约占盲人学校儿童的20%。LCA的临床表型非常严重，其特征是出生时或出生一年内可识别的几种视觉障碍，包括婴儿眼球震颤，各种眼底改变，以及视网膜电图上最小或无反应的反应，每一种都以常染色体隐性遗传模式发生。不幸的是，目前还没有已知的医学或外科干预措施可以改变LCA的自然进程，也没有任何药物治疗显示出调节或减缓其进展的效果。这在一定程度上是由于这种疾病的高度异质性。因此，对LCA患者进行准确的分子诊断和了解其潜在的机制对于设计适当的干预措施是至关重要的。在我们最近的研究中，我们使用定位克隆的方法发现了一个新的LCA疾病基因LCA43。在四个不同种族背景的家系中发现了多个独立的等位基因。与人类视觉系统所需的功能一致，LCA3在小鼠视网膜中高度表达。然而，LCA3在视觉系统中的作用机制尚不清楚。虽然在所有脊椎动物中都保守，但在LCA3中没有明显的蛋白质结构域。此外，还没有建立LCA3的动物模型。为了全面了解LCA3的功能，提出了三个具体的目的：1.确定LCA患者LCA3突变的发生率。特定目的2.研究Lca3在小鼠视网膜中的表达模式。具体目的3.以小鼠为模型系统，对Lca3在视网膜中的功能进行分析。对LCA3功能的全面了解可能会提高LCA的诊断和治疗水平。

DESCRIPTION (provided by applicant): The long term goal of this project is to determine the molecular function of genes involved in human Leber Congenital Amaurosis (LCA). LCA was first described by Theodor Leber as an "intrauterine" form of retinitis pigmentosa about 150 years ago. Now LCA still remains an important cause of blindness, accounting for about 20% of children in schools for the blind. The clinical phenotype of LCA is extremely severe and is characterized by several visual perturbations identifiable at birth or within the first year of life, including infantile nystagmus, a variety of fundus changes, and minimal or absent responses on the electroretinogram, each of which occurs with an autosomal recessive mode of inheritance. Unfortunately, there is still no known medical or surgical intervention that can alter the natural course of LCA, nor has any pharmacologic therapy shown effect on modulating or moderating its progression. This is partially due to the highly heterogeneous nature of this disorder. Therefore, both accurate molecular diagnosis of LCA patients and understanding the underlying mechanisms are essential to design proper intervention for this disease. In our recent studies, we have identified a novel LCA disease gene, LCA43, using a positional cloning approach. Multiple independent alleles have been identified in four families with different ethnic backgrounds. Consistent with a required function in the human visual system, LCA3 is highly expressed in the mouse retina. However, the mechanism of LCA3 function in the visual system is unknown. Although conserved in all vertebrates, no obvious protein domains are apparent in LCA3. In addition, no animal models have been established for LCA3. In order to fully understand its function, three Specific Aims are proposed: Specific Aim 1. Determine the prevalence of LCA3 mutations in LCA patients. Specific Aim 2. Characterize the expression pattern of Lca3 in the mouse retina. Specific Aim 3. Perform functional analysis of Lca3 in the retina using mouse as a model system. A comprehensive understanding of LCA3 function is likely to improve diagnosis and treatment of LCA in the future.