Human Molecular Genetics Advance Access originally published online on May 20, 2007
Human Molecular Genetics 2007 16(14):1699-1707; doi:10.1093/hmg/ddm118
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Mutations in splicing factor PRPF3, causing retinal degeneration, form detrimental aggregates in photoreceptor cells
1 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy, 2 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy and 3 Department of Molecular Genetics, Institute of Ophthalmology, University College London, London, UK
* To whom correspondence should be addressed at: Department of Biomedical Sciences, University of Modena and Reggio Emilia, via Campi 287, 41100 Modena, Italy; Tel: +39 0592055392; Fax: +39 0592055410; E-mail: marigo.valeria{at}unimore.it
Received February 2, 2007; Accepted April 27, 2007
PRPF3 is an element of the splicing machinery ubiquitously expressed, yet mutations in this gene are associated with a tissue-specific phenotype: autosomal dominant retinitis pigmentosa (RP). Here, we studied the subcellular localization of endogenous- and mutant-transfected PRPF3. We found that (i) subcellular distribution of the endogenous wild-type protein co-localizes with small nuclear ribonucleoproteins, partially with a nucleolar marker and accumulates in speckles labeled by SC35; (ii) in human retinas, PRPF3 does not show a distinctive abundance in photoreceptors, the cells affected in RP and (iii) the RP causing mutant PRPF3, differently from the wild-type protein, forms abnormally big aggregates in transfected photoreceptor cells. Aggregation of T494M mutant PRPF3 inside the nucleus triggers apoptosis only in photoreceptor cells. On the basis of the observation that mutant PRPF3 accumulates in the nucleolus and that transcriptional, translational and proteasome inhibition can induce this phenomenon in non-photoreceptor cells, we hypothesize that mutation affects splicing factor recycling. Noteworthy, accumulation of the mutant protein in big aggregates also affects distribution of some other splicing factors. Our data suggest that the mutant protein has a cell-specific dominant effect in rod photoreceptors while appears not to be harmful to epithelial and fibroblast cells.
The first two authors should be regarded as joint First Authors.
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