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.

Public Health Relevance

The main goal of this project is to create a model of the human retinal disease called Leber congenital amaurosis (LCA), which is the leading cause of blindness in infants. In order to create more effective means of diagnosis, prevention, and treatment, we need a more detailed understanding of this devastating disease. Our model for LCA using mouse gene targeting will provide an essential platform for determining the exact defects in the eye and to conduct gene therapy studies to correct such defects.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020540-03
Application #
8410581
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$456,648
Indirect Cost
$164,860
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030