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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Chin, Hemin R
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University of Iowa
Schools of Medicine
Iowa City
United States
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Sheffield, Isaac D; McGee, Mercedes A; Glenn, Steven J et al. (2018) Osteoarthritis-Like Changes in Bardet-Biedl Syndrome Mutant Ciliopathy Mice (Bbs1M390R/M390R): Evidence for a Role of Primary Cilia in Cartilage Homeostasis and Regulation of Inflammation. Front Physiol 9:708
Kerov, Vasily; Laird, Joseph G; Joiner, Mei-Ling et al. (2018) ?2?-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J Neurosci 38:6145-6160
Weihbrecht, Katie; Goar, Wesley A; Carter, Calvin S et al. (2018) Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model. PLoS One 13:e0192755
Haines, Jonathan L; Sheffield, Val C (2017) The molecular genetics of eye diseases. Hum Mol Genet 26:R1
Arafat, Maram; Har-Vardi, Iris; Harlev, Avi et al. (2017) Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet 54:633-639
Kawasaki, Makiri; Izu, Yayoi; Hayata, Tadayoshi et al. (2017) Bardet-Biedl syndrome 3 regulates the development of cranial base midline structures. Bone 101:179-190
Weihbrecht, Katie; Goar, Wesley A; Pak, Thomas et al. (2017) Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in the Eye. Med Res Arch 5:
Hsu, Ying; Garrison, Janelle E; Kim, Gunhee et al. (2017) BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLoS Genet 13:e1007057
Stone, Edwin M; Andorf, Jeaneen L; Whitmore, S Scott et al. (2017) Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 124:1314-1331
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

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