Functional study of a novel gene involved in human retinal disease

与人类视网膜疾病相关的新基因的功能研究

基本信息

批准号：
7923225
负责人：
Hui Wang
金额：
$ 5.22万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923225
关键词：
Accounting Affect Alleles Amino Acid Sequence Animal Model Antibodies Biological Models Birth Blindness Centrosome Child Clinical Collection Data Development Diagnosis Disease Doctor of Philosophy Electroretinography Ethnic group European Family Fellowship Fundus Future Genes Genetic Genotype Goals Guanine Nucleotides Human IMPDH1 gene In Situ Hybridization Individual Inherited Intervention Knock-out Label Laboratories Lead Leber&apos s amaurosis Life Medical Metabolism Molecular Molecular Diagnosis Mus Mutant Strains Mice Mutation Names Nature Operative Surgical Procedures Oral Pathologic Nystagmus Pathway interactions Patients Pattern Peptide Sequence Determination Phenotype Phototransduction Population Preclinical Drug Evaluation Prevalence RNA RPE65 protein Retina Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Schools Screening procedure Signs and Symptoms Staging Staining method Stains System Tertiary Protein Structure Vertebrates Visual Visual system structure Vitamin A base blind cell type clinical phenotype design disease-causing mutation early onset gene function gene replacement gene therapy improved infancy loss of function mutation mouse model mutant novel nucleotide metabolism positional cloning protein transport response

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是确定与人类莱伯先天性黑蒙（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，约占盲校儿童的20%。 LCA 的临床表型极其严重，其特征是在出生时或生命第一年内可识别的几种视觉扰动，包括婴儿期眼球震颤、各种眼底变化以及视网膜电图反应最小或不存在，每种反应都发生在常染色体隐性遗传模式。不幸的是，仍然没有已知的医疗或手术干预可以改变 LCA 的自然病程，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其潜在机制对于设计针对该疾病的适当干预措施至关重要。在我们最近的研究中，我们使用定位克隆方法鉴定了一种新的 LCA 疾病基因 LCA43。在四个不同种族背景的家族中已鉴定出多个独立的等位基因。 LCA3 在小鼠视网膜中高度表达，与人类视觉系统所需的功能一致。然而，LCA3在视觉系统中的功能机制尚不清楚。尽管在所有脊椎动物中都是保守的，但 LCA3 中没有明显的蛋白质结构域。此外，尚未建立LCA3的动物模型。为了充分理解其功能，提出了三个具体目标：具体目标 1. 确定 LCA 患者中 LCA3 突变的患病率。具体目标 2. 表征小鼠视网膜中 Lca3 的表达模式。具体目标 3. 使用小鼠作为模型系统对视网膜中的 Lca3 进行功能分析。对 LCA3 功能的全面了解可能会改善未来 LCA 的诊断和治疗。