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Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration
John J Graziotto1, Michael H Farkas, Kinga Bujakowska
1University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Purpose:
Mutations in genes that produce proteins involved in mRNA splicing, including pre-mRNA processing factors 3, 8, and 31 (PRPF3, 8, and 31), RP9, and SNRNP200 are common causes of the late-onset inherited blinding disorder retinitis pigmentosa (RP). It is not known how mutations in these ubiquitously expressed genes lead to retina-specific disease. To investigate the pathogenesis of the RNA splicing factor forms of RP, the authors generated and characterized the retinal phenotypes of Prpf3-T494M, Prpf8-H2309P knockin mice. The retinal ultrastructure of Prpf31-knockout mice was also investigated.
Methods:
The knockin mice have single codon alterations in their endogenous Prpf3 and Prpf8 genes that mimic the most common disease causing mutations in human PRPF3 and PRPF8. The Prpf31-knockout mice mimic the null alleles that result from the majority of mutations identified in PRPF31 patients. The retinal phenotypes of the gene targeted mice were evaluated by electroretinography (ERG), light, and electron microscopy.
Results:
The RPE cells of heterozygous Prpf3(+/T494M) and Prpf8(+/H2309P) knockin mice exhibited loss of the basal infoldings and vacuolization, with accumulation of amorphous deposits between the RPE and Bruch[b]'s membrane at age two years. These changes were more severe in the homozygous mice, and were associated with decreased rod function in the Prpf3-T494M mice. Similar degenerative changes in the RPE were detected in Prpf31(±) mice at one year of age.
Conclusions:
The finding of similar degenerative changes in RPE cells of all three mouse models suggests that the RPE may be the primary cell type affected in the RNA splicing factor forms of RP. The relatively late-onset phenotype observed in these mice is consistent with the typical adult onset of disease in patients with RP.
Insights
Mutations in RNA splicing factors cause retinitis pigmentosa (RP). Mouse models show retinal pigment epithelium (RPE) degeneration, suggesting RPE is the primary affected cell type in this blinding disorder.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Mutations in mRNA splicing factor genes (PRPF3, PRPF8, PRPF31) are linked to retinitis pigmentosa (RP).
- The retina-specific pathology caused by these ubiquitously expressed genes remains unclear.
Purpose of the Study:
- To investigate the pathogenesis of RNA splicing factor-related RP.
- To characterize the retinal phenotypes of mouse models mimicking human mutations in PRPF3, PRPF8, and PRPF31.
Main Methods:
- Generated knockin mice with specific mutations in Prpf3 and Prpf8 genes.
- Created Prpf31-knockout mice to model null alleles.
- Evaluated retinal phenotypes using electroretinography, light microscopy, and electron microscopy.
Main Results:
- All three mouse models exhibited retinal pigment epithelium (RPE) degeneration.
- Observed RPE changes included loss of basal infoldings, vacuolization, and deposit accumulation.
- Prpf3-T494M mice showed decreased rod function, correlating with RPE changes.
Conclusions:
- The retinal pigment epithelium (RPE) is likely the primary cell type affected in RNA splicing factor forms of RP.
- The observed late-onset phenotypes in mouse models align with typical adult-onset RP in patients.