RNA Splicing Factor Mutations That Cause Retinitis Pigmentosa Result in Circadian Dysregulation

Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindne...

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Bibliographic Details
Published in:Journal of biological rhythms 2020-02, Vol.35 (1), p.72-83
Main Authors: Shakhmantsir, Iryna, Dooley, Scott J., Kishore, Siddharth, Chen, Dechun, Pierce, Eric, Bennett, Jean, Sehgal, Amita
Format: Article
Language:English
Subjects:
Animal models
Biological clocks
Bioluminescence
Blindness
Cell culture
Circadian rhythm
Circadian rhythms
Epithelium
Eye
Fibroblasts
Fruit flies
Gene expression
Homology
Mutation
Phenotypes
Retina
Retinal pigment epithelium
Retinitis
Retinitis pigmentosa
Ribonucleic acid
RNA
Splicing factors
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Summary:Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 (Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.
ISSN:0748-7304
1552-4531
DOI:10.1177/0748730419887876