Genetics of Early Onset Retinal Diseases
The goal of this research project is to identify novel genes that are involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes causing Leber congenital amaurosis (LCA) , the most common hereditary cause of visual impairment in infants and children, will be identified using a positional cloning approach. Discovery of novel LCA genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in LCA disease genes also cause other retinal dystrophies, isolation of additional LCA disease genes will provide important insights concerning the molecular mechanisms underlying both LCA and retinal diseases in general.
LCA is a set of inherited, early onset retinopathies that affect about 1 in 15,000 in the general population and account for more than 5% of all retinal dystrophies . Currently, mutations in at least ten genes have been associated with recessive LCA. Studies of these genes have lead to the development of novel pharmaceutical intervention and gene therapy. However, about 40% of familial cases cannot be explained by mutations in these known LCA genes, representing one of the most significant gaps in our understanding of LCA . To clone additional LCA disease genes, we have collected DNA samples from 38 consanguineous families with LCA. Our initial mutation analysis has suggested that 28 of these families are likely due to mutations in novel LCA disease genes. In this proposal, we plan to use positional cloning to identify the underlying mutations carried by these 28 families using a combinatorial approach of molecular biology and bioinformatics.
Our Specific Aims are to:
- Perform Positional Cloning of the LCA3 Gene
- Identify Novel LCA Loci and Genes
- Continued Enrollment and Mutation Analysis of LCA Families
Progress toward these goals is likely to identify new LCA genes whose subsequent study will lead to new insights of disease mechanisms as well as lay the foundation for developing new diagnoses and treatment methods.
Relevance of the project to IDDRC mission:
The project aims directly at identifying novel genes involved in human retinal developmental defects. Furthermore, we are interested in utilizing the knowledge gained from the project to design better diagnosis and treatment of the disease. Many genes identified so far that underlying the retinal diseases also have broad implications on other human conditions, including mental retardation.