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.
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.
|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|
|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|
|Heon, Elise; Kim, Gunhee; Qin, Sophie et al. (2016) Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet 25:2283-2294|
|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|
|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|
|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|
|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|
|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|
|Chamling, Xitiz; Seo, Seongjin; Searby, Charles C et al. (2014) The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome. PLoS Genet 10:e1004083|
|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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