Functional study of a novel gene involved in human retinal disease

描述（由申请人提供）：本项目的长期目标是确定与人类先天性利伯黑蒙（LCA）相关的基因的分子功能。大约150年前，Theodor Leber首次将LCA描述为视网膜色素变性的“子宫内”形式。目前，LCA仍是一个重要的致盲原因，约占盲校儿童的20%。LCA的临床表型非常严重，其特征在于出生时或出生后第一年内可识别的几种视觉扰动，包括婴儿眼球震颤，各种眼底变化，以及视网膜电图上的最小或无反应，其中每一种都以常染色体隐性遗传方式发生。不幸的是，仍然没有已知的药物或手术干预可以改变LCA的自然过程，也没有任何药物治疗显示出调节或缓和其进展的效果。这部分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潜在的机制对于设计针对这种疾病的适当干预至关重要。在我们最近的研究中，我们已经确定了一个新的LCA疾病基因，LCA 43，使用定位克隆方法。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。与人类视觉系统中所需的功能一致，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是保守的，但在LCA3中没有明显的蛋白质结构域。此外，尚未建立LCA 3的动物模型。为了充分了解其功能，提出了三个具体目标：具体目标1。确定LCA患者中LCA 3突变的患病率。具体目标2。表征Lca3在小鼠视网膜中的表达模式。具体目标3。以小鼠为模型系统，对Lca3在视网膜中的功能进行分析。对LCA 3功能的全面了解可能会改善未来LCA的诊断和治疗。

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.