Functional study of a novel gene involved in human retinal disease

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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.