We propose to continue to study a genetically heterogeneous, autosomal recessive form of retinal degeneration known as Bardet-Biedl syndrome (BBS). BBS is a pleiotropic disorder with the primary clinical features of pigmentary retinopathy, obesity, polydactyly, learning disabilities, renal abnormalities and hypogenitalism. I is also associated with hypertension, diabetes mellitus and congenital heart defects. The retinal degeneration of BBS is early onset and typically leads to blindness in the second decade of life. However, there is variation in the course and severity of BBS retinopathy. At least sixteen BBS genes have been reported to date and additional BBS genes, accounting for approximately 30% of cases, remain to be discovered. It has been observed that the BBS phenotype varies greatly between and within families and this variability in expressivity indicates that other genes modify the phenotype. Such genetic modifiers may be the BBS genes themselves, or other genes that do not independently cause BBS when mutated. The identification of additional BBS genes will be important to fully understand the role of genetic modification in this disorder, and the study o BBS is useful in understanding mechanisms underlying genetic complexity. The fact that we have identified two protein complexes involved in BBS (the BBSome and the BBS chaperone complex) provides us with the opportunity to study how interactions within and between protein complexes contribute to genetic complexity at the biochemical level. In addition, access to a number of animal models provides us with the opportunity to determine the potential modifying effects of other biochemical pathways on BBS phenotypes. In the proposed studies, we will identify novel BBS genes (Specific Aim 1).
In Specific Aim 2, we will evaluate BBS as a complex disorder in two model organisms (zebrafish and mice).
In Specific Aim 3, we will evaluate the extent to which specific biochemical pathways modify BBS phenotypes. Our studies will lead to a better understanding of cilia-related retinopathies, complex disease, and the interactions of biochemical pathways. We propose to perform the first biochemical studies to determine whether a combination of mutations in more than one BBS gene impacts BBSome formation and downstream pathways dependent on the BBSome. The proposed studies have the potential to identify targets for treatment of BBS and other retinopathies.

Public Health Relevance

The successful completion of this project will lead to insights into disease mechanisms causing inherited forms of blindness, as well as insights into common major human disorders including obesity, hypertension and diabetes. The results will potentially improve diagnosis, genetic risk assessment, and treatment of these disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Special Emphasis Panel (DPVS)
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Shen, Grace L
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University of Iowa
Schools of Medicine
Iowa City
United States
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Zhang, Yan; Seo, Seongjin; Bhattarai, Sajag et al. (2014) BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet 23:40-51
Mei, Xue; Westfall, Trudi A; Zhang, Qihong et al. (2014) Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms. Dev Biol 392:245-55
Chamling, Xitiz; Seo, Seongjin; Bugge, Kevin et al. (2013) Ectopic expression of human BBS4 can rescue Bardet-Biedl syndrome phenotypes in Bbs4 null mice. PLoS One 8:e59101
Zhang, Qihong; Yu, Dahai; Seo, Seongjin et al. (2012) Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome. J Biol Chem 287:20625-35
Drack, Arlene V; Dumitrescu, Alina V; Bhattarai, Sajag et al. (2012) TUDCA slows retinal degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in Bardet-Biedl syndrome type 1 mice. Invest Ophthalmol Vis Sci 53:100-6
Zhang, Qihong; Seo, Seongjin; Bugge, Kevin et al. (2012) BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Hum Mol Genet 21:1945-53
Guo, Deng-Fu; Beyer, Andreas M; Yang, Baoli et al. (2011) Inactivation of Bardet-Biedl syndrome genes causes kidney defects. Am J Physiol Renal Physiol 300:F574-80
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Wright, Kevin J; Baye, Lisa M; Olivier-Mason, Anique et al. (2011) An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev 25:2347-60

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