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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021237-04
Application #
8730659
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chekuri, Anil; Guru, Aditya A; Biswas, Pooja et al. (2018) IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. Hum Genet 137:447-458
Villanueva, Adda; Biswas, Pooja; Kishaba, Kameron et al. (2018) Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent. Ophthalmic Genet 39:73-79
Biswas, Pooja; Naeem, Muhammad Asif; Ali, Muhammad Hassaan et al. (2018) Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree. Adv Exp Med Biol 1074:219-228
Li, Lin; Jiao, Xiaodong; D'Atri, Ilaria et al. (2018) Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. PLoS Genet 14:e1007504
Branham, Kari; Guru, Aditya A; Kozak, Igor et al. (2018) Identification of Novel Deletions as the Underlying Cause of Retinal Degeneration in Two Pedigrees. Adv Exp Med Biol 1074:229-236
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Godisela, Kishore Kumar; Reddy, Singareddy Sreenivasa; Kumar, Chekkilla Uday et al. (2017) Impact of obesity with impaired glucose tolerance on retinal degeneration in a rat model of metabolic syndrome. Mol Vis 23:263-274
D'Antonio, Matteo; Woodruff, Grace; Nathanson, Jason L et al. (2017) High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells. Stem Cell Reports 8:1101-1111
Li, Lin; Chen, Yabin; Jiao, Xiaodong et al. (2017) Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. Invest Ophthalmol Vis Sci 58:2218-2238
Greenwald, William W; Li, He; Smith, Erin N et al. (2017) Pgltools: a genomic arithmetic tool suite for manipulation of Hi-C peak and other chromatin interaction data. BMC Bioinformatics 18:207

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