The goal of the studies proposed in this application is to enhance our understanding of retinal degeneration (RD) by identifying additional genes associated with recessive RD and determining the underlying molecular mechanisms. Known genes are estimated to contribute to approximately 30% of cases of recessive RD. The studies proposed here will test the hypothesis that identification of remaining genes for RD will assist in understanding the mechanisms underlying these diseases. Populations with high inbreeding and consanguineous marriages are best suited for identifying genes associated with recessive retinal conditions. The molecular basis of hereditary retinal diseases in inbred populations from Pakistan, India, and Mexico has not been well studied. Preliminary analyses have indicated the involvement of new genes in causing RD in these populations. In this application, studies are focused on identifying new genes for recessive RD by analyzing consanguineous families from India, Pakistan, Mexico, and the United States and understanding the mechanisms underlying degeneration. Studies using exome capture and sequencing have been proven to be efficient in identifying gene mutations causing hereditary conditions. Genes associated with recessive RD in a cohort of consanguineous families will be identified by analyzing the exome sequence. The studies proposed in this application will be carried out with the following specific aims: (1) to screen probands for mutations in known RD genes by using genotyping arrays and/or by analyzing variants in the exome, (2) to identify new genes involved in causing RD by analyzing the exome sequence of affected and unaffected members of pedigrees with RD, and (3) to understand the mechanisms underlying the disease process by determining the function of novel RD genes we will identify and evaluating the effect of mutations on the encoded protein. These new RD genes may assist in understanding the molecular pathology of RD and help in improving our understanding of the role of previously identified RD genes and the pathways critical for normal function of the retina. The outcome of these studies will assist in providing specific diagnoses and prognoses to patients and in identifying specific therapeutic targets to develop therapies to slow the progression of these conditions, delay their onset, or treat them.

Public Health Relevance

In this application we propose to identify new genes causing recessive retinal degeneration and understand the mechanism underlying the disease pathology. These studies will help in providing specific diagnoses, prognoses and in developing therapies for these conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Gustafson, Kevin; Duncan, Jacque L; Biswas, Pooja et al. (2017) Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree. Genes (Basel) 8:
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