TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein

We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demo...

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Bibliographic Details
Published in:Human molecular genetics 2011-03, Vol.20 (5), p.975-987
Main Authors: CHAKAROVA, Christina F, KHANNA, Hemant, CHEETHAM, Michael, KOENEKOOP, Robert K, RIOS, Rosa M, MATTER, Karl, WOLFRUM, Uwe, SWAROOP, Anand, BHATTACHARYA, Shomi S, SHAH, Amna Z, PATIL, Suresh B, SEDMAK, Tina, MURGA-ZAMALLOA, Carlos A, PAPAIOANNOU, Myrto G, NAGEL-WOLFRUM, Kerstin, LOPEZ, Irma, MUNRO, Peter
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
Cells, Cultured
Centrosome - metabolism
Cilia - genetics
Cilia - metabolism
Danio rerio
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Humans
Medical sciences
Mice
Molecular and cellular biology
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Ophthalmology
Photoreceptor Cells - metabolism
Protein Transport
Retina - metabolism
Retinal Degeneration - genetics
Retinal Degeneration - metabolism
Retinopathies
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Zebrafish
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Summary:We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS is a novel component of the photoreceptor sensory cilium, which is a modified primary cilium involved with polarized trafficking of proteins. In photoreceptors, TOPORS localizes primarily to the basal bodies of connecting cilium and in the centrosomes of cultured cells. Morpholino-mediated silencing of topors in zebrafish embryos demonstrates in another species a comparable retinal problem as seen in humans, resulting in defective retinal development and failure to form outer segments. These defects can be rescued by mRNA encoding human TOPORS. Taken together, our data suggest that TOPORS may play a key role in regulating primary cilia-dependent photoreceptor development and function. Additionally, it is well known that mutations in other ciliary proteins cause retinal degeneration, which may explain why mutations in TOPORS result in the same phenotype.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddq543