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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Shen, Grace L
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University of Iowa
Schools of Medicine
Iowa City
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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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