A major stated research priority of the National Eye Institute is """"""""to identify the genes involved in retinal degenerative diseases"""""""". Although numerous genes causing retinal degeneration have been discovered, many remain to be identified, and novel approaches to the identification of additional retinal degeneration genes are needed. The goal of this project is the identification of genes that cause human retinal degeneration, specifically genes causing a syndromic form of photoreceptor degeneration known as Bardet- Biedl syndrome (BBS), as well as autosomal recessive retinitis pigmentosa (ARRP). BBS is a genetically heterogeneous disorder for which eleven genes have been identified to date, and for which there is strong evidence that multiple additional genes remain to be discovered. Similarly, the known ARRP genes account for less than half of all cases, a finding that indicates that numerous retinal disease genes remain to be discovered. Historically, the identification of disease genes has relied on genetic mapping and positional cloning using large affected families. The lack of large families for many diseases makes it necessary to use alternative strategies. In this application, we propose to use single nucleotide polymorphism (SNP) genotyping of small consanguineous families to identify candidate regions of homozygosity in combination with comparative genomic data and novel eye gene expression data to identify BBS genes. We present preliminary data showing the effectiveness of this approach. In addition, we will use a novel highly cost effective strategy to screen candidate genes for mutations in ARRP patients. In addition to disease gene discovery, we propose to further develop and validate methods for the functional analysis of retinal disease candidate genes using the zebrafish model system. Analysis of function is an important step in the verification of candidate genes as a cause of retinal diseases. The development, validation and utilization of a high throughput assay to verify disease causation is an important component of the overall goal to identify new retinal disease genes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017168-05
Application #
8082667
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Chin, Hemin R
Project Start
2007-06-01
Project End
2012-11-30
Budget Start
2011-09-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$563,706
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Guo, Deng-Fu; Cui, Huxing; Zhang, Qihong et al. (2016) The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. PLoS Genet 12:e1005890
Heon, Elise; Kim, Gunhee; Qin, Sophie et al. (2016) Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet 25:2283-2294
Scott, C Anthony; Marsden, Autumn N; Slusarski, Diane C (2016) Automated, high-throughput, in vivo analysis of visual function using the zebrafish. Dev Dyn 245:605-13
Muhammad, Emad; Levitas, Aviva; Singh, Sonia R et al. (2015) PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction. Hum Mol Genet 24:7227-40
Datta, Poppy; Allamargot, Chantal; Hudson, Joseph S et al. (2015) Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A 112:E4400-9
Haziza, Sitvanit; Magnani, Roberta; Lan, Dima et al. (2015) Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function. PLoS Genet 11:e1005388
Starks, Rachel D; Beyer, Andreas M; Guo, Deng Fu et al. (2015) Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. PLoS Genet 11:e1005311
Goodman, Corey W; Major, Heather J; Walls, William D et al. (2015) CNV-ROC: A cost effective, computer-aided analytical performance evaluator of chromosomal microarrays. J Biomed Inform 54:106-13
Agassandian, Khristofor; Patel, Milan; Agassandian, Marianna et al. (2014) Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model. PLoS One 9:e93484
Zhang, Yan; Seo, Seongjin; Bhattarai, Sajag et al. (2014) BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet 23:40-51

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