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Open Access Research article

Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa

Jun Yin13, Jan Brocher14, Utz Fischer2 and Christoph Winkler1*

Author Affiliations

1 Department of Biological Sciences; National University of Singapore; 117543, Singapore

2 Department of Biochemistry, Biocenter, University of Wuerzburg, 97074, Germany

3 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, One Shields Ave, Davis, CA 95616 USA

4 Division of Experimental Orthopaedics, Orthopaedic University Hospital of Heidelberg, Schlierbacher Landstrasse 200, 69115 Heidelberg, Germany

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Molecular Neurodegeneration 2011, 6:56  doi:10.1186/1750-1326-6-56

Published: 30 July 2011

Abstract

Background

Retinitis pigmentosa (RP) is an inherited eye disease characterized by the progressive degeneration of rod photoreceptor cells. Mutations in pre-mRNA splicing factors including PRPF31 have been identified as cause for RP, raising the question how mutations in general factors lead to tissue specific defects.

Results

We have recently shown that the zebrafish serves as an excellent model allowing the recapitulation of key events of RP. Here we use this model to investigate two pathogenic mutations in PRPF31, SP117 and AD5, causing the autosomal dominant form of RP. We show that SP117 leads to an unstable protein that is mislocalized to the rod cytoplasm. Importantly, its overexpression does not result in photoreceptor degeneration suggesting haploinsufficiency as the underlying cause in human RP patients carrying SP117. In contrast, overexpression of AD5 results in embryonic lethality, which can be rescued by wild-type Prpf31. Transgenic retina-specific expression of AD5 reveals that stable AD5 protein is initially localized in the nucleus but later found in the cytoplasm concurrent with progressing rod outer segment degeneration and apoptosis. Importantly, we show for the first time in vivo that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors.

Conclusion

Our data suggest that distinct mutations in Prpf31 can lead to photoreceptor degeneration through different mechanisms, by haploinsufficiency or dominant-negative effects. Analyzing the AD5 effects in our animal model in vivo, our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.

Keywords:
Retinitis pigmentosa (RP); PRPF31; AD5 mutation; SP117 mutation; haploinsufficiency; dominant-negative; rod degeneration; apoptosis; splicing defect