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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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Baylor College of Medicine
Schools of Medicine
United States
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Dharmat, Rachayata; Eblimit, Aiden; Robichaux, Michael A et al. (2018) SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium. J Cell Biol 217:2851-2865
Eblimit, Aiden; Zaneveld, Smriti Agrawal; Liu, Wei et al. (2018) NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype. Exp Eye Res 173:32-43
Eblimit, Aiden; Agrawal, Smriti Akshay; Thomas, Kandace et al. (2018) Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice. Exp Eye Res 166:120-130
Gui, Shupeng; Rice, Andrew P; Chen, Rui et al. (2017) A scalable algorithm for structure identification of complex gene regulatory network from temporal expression data. BMC Bioinformatics 18:74
Chen, Yong; Zhao, Li; Wang, Yi et al. (2017) SeqCNV: a novel method for identification of copy number variations in targeted next-generation sequencing data. BMC Bioinformatics 18:147
Agrawal, Smriti A; Burgoyne, Thomas; Eblimit, Aiden et al. (2017) REEP6 deficiency leads to retinal degeneration through disruption of ER homeostasis and protein trafficking. Hum Mol Genet 26:2667-2677
Arno, Gavin; Agrawal, Smriti A; Eblimit, Aiden et al. (2016) Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. Am J Hum Genet 99:1305-1315
Zhao, Li; Chen, Yiyun; Bajaj, Amol Onkar et al. (2016) Integrative subcellular proteomic analysis allows accurate prediction of human disease-causing genes. Genome Res 26:660-9
Zhong, H; Eblimit, A; Moayedi, Y et al. (2015) AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa. Gene Ther 22:619-27
Eblimit, Aiden; Nguyen, Thanh-Minh T; Chen, Yiyun et al. (2015) Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina. Hum Mol Genet 24:1584-601

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