Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-07-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/56 |
| _version_ | 1811276732258320384 |
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| author | Brocher Jan Yin Jun Fischer Utz Winkler Christoph |
| author_facet | Brocher Jan Yin Jun Fischer Utz Winkler Christoph |
| author_sort | Brocher Jan |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 <it>PRPF31</it>, 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 <it>in vivo </it>that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors.</p> <p>Conclusion</p> <p>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 <it>in vivo</it>, our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.</p> |
| first_indexed | 2024-04-13T00:03:01Z |
| format | Article |
| id | doaj.art-f116a4f606764d51868f25790c7c366d |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-13T00:03:01Z |
| publishDate | 2011-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-f116a4f606764d51868f25790c7c366d2022-12-22T03:11:19ZengBMCMolecular Neurodegeneration1750-13262011-07-01615610.1186/1750-1326-6-56Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosaBrocher JanYin JunFischer UtzWinkler Christoph<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 <it>PRPF31</it>, 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 <it>in vivo </it>that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors.</p> <p>Conclusion</p> <p>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 <it>in vivo</it>, our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.</p>http://www.molecularneurodegeneration.com/content/6/1/56Retinitis pigmentosa (RP)PRPF31AD5 mutationSP117 mutationhaploinsufficiencydominant-negativerod degenerationapoptosissplicing defect |
| spellingShingle | Brocher Jan Yin Jun Fischer Utz Winkler Christoph Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa Molecular Neurodegeneration Retinitis pigmentosa (RP) PRPF31 AD5 mutation SP117 mutation haploinsufficiency dominant-negative rod degeneration apoptosis splicing defect |
| title | Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa |
| title_full | Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa |
| title_fullStr | Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa |
| title_full_unstemmed | Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa |
| title_short | Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa |
| title_sort | mutant prpf31 causes pre mrna splicing defects and rod photoreceptor cell degeneration in a zebrafish model for retinitis pigmentosa |
| topic | Retinitis pigmentosa (RP) PRPF31 AD5 mutation SP117 mutation haploinsufficiency dominant-negative rod degeneration apoptosis splicing defect |
| url | http://www.molecularneurodegeneration.com/content/6/1/56 |
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