The long-term objectives of the proposed research are to improve our understanding of the molecular bases of inherited retinal degenerations (IRDs) so that therapies can be developed for these blinding disorders. IRDs are characterized by progressive dysfunction and death of photoreceptor cells, and occur in non-syndromic and syndromic forms. IRDs are genetically heterogeneous, with over 140 disease genes identified to date. However, the identified mutations account for only ~50% of patients with these disorders and the mechanisms by which the majority of the identified mutations cause photoreceptor cell death remain to be determined.
The Aims of the proposed research are based on the recognition that photoreceptor outer segments are specialized sensory cilia. Work on retinitis pigmentosa 1 (RP1) lead the applicant to appreciate that like other cilia, photoreceptor sensory cilia (PSCs) consist of a basal body, axoneme, and specialized membrane domain. This is important because it connects IRDs at a mechanistic level to a larger class of systemic cilia disorders such as Bardet Biedl and Usher syndromes. From this connection, it is evident that many IRDs are caused by mutations in genes that encode proteins that are required for the function of PSCs and other cilia. The focus of Aim 1 will be continued investigations of the PSC protein RP1. Through studies of RP1 protein function in vitro and in vivo it has been shown that RP1 is a photoreceptor microtubule-associated protein (MAP) that is part of the photoreceptor axoneme, and is required for organization of outer segment structure. Recent data have lead to the hypothesis that RP1 is part of a complex of proteins that function in PSCs and other cilia to organize these structures. The investigations to test this hypothesis and study the pathogenesis of RP1 disease in Aim 1 are thus integrated with the studies of additional novel PSC proteins and genes that will be the focus of Aims 2 and 3. To facilitate work on RP1 and initiate studies of PSCs from a broader perspective a detailed proteomic analysis of mouse PSC complexes was performed. The PSC complex proteome identified by = 3 unique peptides contains 1968 proteins, including many novel PSC proteins. The locations of a subset of novel proteins in the PSC have been validated, confirming the accuracy of the proteome. The PSC complex proteome opens novel avenues for studies of how these cilia are built and maintained, and how these processes are disrupted in human disease.
In Aim 2, the hypothesis that novel cilia proteins detected in the PSC complex proteome are important for PSC structure and function will be tested by studying a selected subset of novel PSC proteins.
In Aim 3, the hypothesis that genes that encode novel PSC complex proteins are good candidate IRD disease genes will be tested by screening the genes that encode functionally validated PSC proteins for mutations that cause recessive and dominant IRDs.
Inherited retinal degenerations are common causes of blindness. These disorders are caused by mutations in genes that encode proteins which are required for proper function of the light sensitive photoreceptor cells of the retina. The goals of the proposed research are to identify mutations responsible for some forms of inherited retinal degeneration, and investigate how the identified mutations lead to blindness so that therapies can be developed to prevent vision loss from these diseases.
|Comander, Jason; Weigel-DiFranco, Carol; Maher, Matthew et al. (2017) The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa. Genes (Basel) 8:|
|Men, Clara J; Bujakowska, Kinga M; Comander, Jason et al. (2017) The importance of genetic testing as demonstrated by two cases of CACNA1F-associated retinal generation misdiagnosed as LCA. Mol Vis 23:695-706|
|Bujakowska, Kinga M; Fernandez-Godino, Rosario; Place, Emily et al. (2017) Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations. Genet Med 19:643-651|
|Greenwald, Scott H; Charette, Jeremy R; Staniszewska, Magdalena et al. (2016) Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease. Am J Pathol 186:1925-1938|
|Falk, Marni J; Gai, Xiaowu; Shigematsu, Megumi et al. (2016) A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression. RNA Biol 13:477-85|
|Bujakowska, Kinga M; Zhang, Qi; Siemiatkowska, Anna M et al. (2015) Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet 24:230-42|
|Consugar, Mark B; Navarro-Gomez, Daniel; Place, Emily M et al. (2015) Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing. Genet Med 17:253-261|
|Koboldt, Daniel C; Larson, David E; Sullivan, Lori S et al. (2014) Exome-based mapping and variant prioritization for inherited Mendelian disorders. Am J Hum Genet 94:373-84|
|Daiger, Stephen P; Bowne, Sara J; Sullivan, Lori S et al. (2014) Application of next-generation sequencing to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). Adv Exp Med Biol 801:123-9|
|Bujakowska, Kinga M; Consugar, Mark; Place, Emily et al. (2014) Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci 55:8488-96|
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