Molecular Mechanisms of Human Retinal Disease

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The long-term goal of this project is to improve both the diagnoses and the treatments of Leber congenital amaurosis (LCA). LCA is a set of inherited, early onset retinopathies that affect about 1 in 50,000 in the general U.S. population and accounts for more than 5% of all retinal dystrophies. The clinical phenotypes of LCA classically follow autosomal recessive modes of inheritance, are often severe, and are 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. Consistent with this clinical heterogeneity, the molecular basis for LCA is also heterogeneous, with mutations in fifteen different genes associated with LCA. We recently identified the causative gene associated with LCA3, named SPATA7, which encodes a highly conserved but novel protein of unknown function and for which no animal models have been established. We have created null alleles of the mouse Spata7 gene and have shown that Spata7 homozygotes are viable but present severe retinal defects, recapitulating the major features of the human LCA3 condition. Significantly, SPATA7 mutations are associated with both LCA and early-onset retinitis pigmentosa (RP), suggesting that a detailed understanding of SPATA7 function could have broad implications for our ability to diagnose, prevent, and treat human retinal diseases. In this proposal, our Specific Aims are to: Specific Aim 1. Study a mouse model for LCA3: Spata7 null mutant analysis, Specific Aim 2. Define the role of Spata7 in retinitis pigmentosa, Specific Aim 3. Determine the prevalence of SPATA7 mutations in ocular disease patients. Together these studies will greatly increase our understanding of the mechanisms of human retinal disease and improve our ability to diagnose, prevent, and treat LCA and other human ocular dystrophies.