May 2005
Volume 46, Issue 13
ARVO Annual Meeting Abstract  |   May 2005
Haploinsufficiency of Prpf8 Does Not Cause Retinal Degeneration
Author Affiliations & Notes
  • B.M. Deramaudt
    Ophthalmology, Univ of Pennsylvania, Philadelphia, PA
  • C.F. Inglehearn
    Molecular Medicine Unit, Leeds University, Leeds, United Kingdom
  • E.A. Pierce
    Ophthalmology, Univ of Pennsylvania, Philadelphia, PA
  • Footnotes
    Commercial Relationships  B.M. Deramaudt, None; C.F. Inglehearn, None; E.A. Pierce, None.
  • Footnotes
    Support  E. Matilda Ziegler Foundation, RPB, Paul and Evanina Mackall Trust
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 5263. doi:
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      B.M. Deramaudt, C.F. Inglehearn, E.A. Pierce; Haploinsufficiency of Prpf8 Does Not Cause Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5263.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose:Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous group of inherited retinal degenerations. Most forms of RP are caused by mutations in retina specific genes, but three forms of dominant RP have recently been found to be due to mutations in components of the spliceosome, including RP11, RP13 and RP18, caused by mutations in Pre–RNA–Processing Factors (PRPF) 31, 8 and 3, respectively. To date, 7 different kind of mutations affecting the PRPF8 gene leading to Retinitis Pigmentosa 13 (RP13) have been identified, all of them located in the final exon (number 42) of PRPF8. To understand how mutations in the ubiquitously expressed PRPF8 protein lead to a retina specific phenotype and alter RNA splicing in the retina we generated mice in which the highly conserved Prpf8 gene is knocked–out. Methods:We searched the BayGenomics Gene Trap Consortium ( for an ES cell line with a disruption of Prpf8. We obtained clone RRI–203, which has the pGT2lxf gene trap vector inserted into the Prpf8 gene at the end of exon 16, leading to the expression of a fusion protein containing the first 15 exons of Prpf8 upstream the ß–Geo fusion protein. We injected the RRI–203 ES cells into blastocysts to generate chimeric founder mice. Chimeric mice were backcrossed with C57BL/6 mice to generate mice heterozygous for the gene trap allele. The visual function of heterozygous mice was evaluated by electroretinograph (ERG) analysis. Retinal structure was evaluated by histology. Results: Male and female heterozygous mice are healthy and fertile. ERG analysis indicates that heterozygotes have rod a– and b–wave function equal to that of littermate controls up to 11 months of age. Similarly, the retinas of heterozygous mutant mice do not show any structural abnormalities. Intercrosses of heterozygous mice fail to generate homozygous mutants. Conclusions:The normal retinal function observed in heterozygous Prpf8 mutant mice suggests that haploinsufficiency of Prpf8 does not cause retinal degeneration. This implies that the severe retinal degeneration observed in patients with mutations in exon 42 of PRPF8 is due to a toxic effect of the mutant proteins on retinal function. We will test this hypothesis by evaluating the phenotype of Prpf8–H2309P knockin mice which we have also produced. The failure of intercrosses to produce homozygous mutant animals suggests RNA splicing is disrupted in the absence of Prpf8.

Keywords: retinitis • electroretinography: non-clinical • transgenics/knock-outs 

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