TY  - JOUR
A1  - Yin, Jun
A1  - Brocher, Jan
A1  - Fischer, Utz
A1  - Winkler, Christoph
T1  - Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa
T2  - Molecular neurodegeneration
N2  - 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.
KW  - Factor gene PRPF31
KW  - TRI-SNRNP
KW  - Transgenic zebrafish
KW  - Homebox gene
KW  - Chinese family
KW  - Mutations
KW  - RP11
KW  - Expression
KW  - Disease
KW  - Protein
KW  - Retinitis pigmentosa (RP)
KW  - PRPF31
KW  - AD5 mutation
KW  - SP117 mutation
KW  - haploinsufficiency
KW  - dominant-negative
KW  - rod degeneration
KW  - apoptosis
KW  - splicing defect
Y1  - 2011
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/14109
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-141090
VL  - 6
IS  - 56
ER  -