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

Shakhmantsir, Iryna; Dooley, Scott J.; Kishore, Siddharth; Chen, Dechun; Pierce, Eric A.; Bennett, Jean; Sehgal, Amita

doi:10.1177/0748730419887876

Cited by 6 publications

(5 citation statements)

References 57 publications

(99 reference statements)

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“…4D). Disruption of behavioral and retinal circadian rhythms has recently been reported in a mouse model of RP due to an RNA splicing factor mutation [48], suggesting commonality in pathology. Overall these changes suggest that the cones undergo comprehensive modifications including metabolism and circadian activity during the degeneration/regeneration scenario.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic remodeling of the retina in a Zebrafish model of Retinitis Pigmentosa

Santhanam

Shihabeddin

Wei

et al. 2022

Preprint

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Inherited retinal degenerative diseases such as Retinitis Pigmentosa (RP) result in progressive loss of photoreceptors until an individual is completely blind. A hallmark of these diseases is progressive structural and functional remodeling of the remaining retinal neurons as rod photoreceptors are lost. While many studies focus on regenerative or bionic therapies to restore vision, extensive remodeling of retinal cell types throughout the course of retinal degenerative diseases stands as a barrier for successful implementation of these strategies. As a window onto the molecular basis of remodeling, we have performed a comparative analysis of single-cell transcriptome data from adult Zebrafish retina of wild-type and a P23H mutant rhodopsin model of RP. In addition to providing a benchmark atlas of retinal cell type transcriptomes in the wild-type adult Zebrafish retina, we find transcriptional changes in essentially all retinal cell types in the P23H model. Increased oxidative stress is evident not only in the rods but also in cones, retinal pigmented epithelium (RPE) and to a lesser extent in amacrine and bipolar cells. Metabolic changes increasing oxidative metabolism and glycolysis are found in rods and cones, while evidence of increased activity of the mitochondrial electron transport chain is found in retinal ganglion cells (RGCs). Evidence of synaptic remodeling is found throughout the retina, with changes to increase synaptic transmission in photoreceptors and bipolar cells, increased ionotropic glutamate receptors in amacrine and ganglion cells, and dendritic and axon remodeling throughout. Surprisingly, RPE, cones and bipolar cells in the P23H retinas also have increased expression of genes involved in circadian rhythm regulation. While this model system undergoes continuous regeneration, ongoing remodeling impacts the entire retina. This comprehensive transcriptomic analysis provides a molecular road map to understand how the retina remodels in the context of chronic retinal degeneration with ongoing regeneration.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic remodeling of the retina in a Zebrafish model of Retinitis Pigmentosa

Santhanam

Shihabeddin

Wei

et al. 2022

Preprint

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“…For example, RPE cells were studied at a preclinical assay conducted by Shakhmantsir et al on Prpf8 knock-in mice carrying a missense mutation responsible for RP in some patients. They concluded that circadian dysregulation could also contribute to retinal damage together with other push factors in the disease pathogenesis [ 58 ]. Turning to our study, circulating solubilized TNF-αRII was used as a biomarker of cellular inflammation due to its relationship with intracellular adhesion molecules (ICAM) and other inflammatory factors [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Stress and sleep deprivation-related biomarkers in saliva in patients with retinitis pigmentosa

Mateos-Olivares,

Pastor-Idoate,

Martín-Vallejo

et al. 2024

PLoS ONE

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Purpose Patients with Retinitis Pigmentosa (RP) commonly experience sleep-related issues and are susceptible to stress. Moreover, variatiaons in their vision are often linked to anxiety, stress and drowsiness, indicating that stress and sleep deprivation lead to a decline in vision, and vision improves when both are mitigated. The objective of this study was to investigate the utility of salivary biomarkers as biochemical indicators of anxiety and sleep deprivation in RP patients. Methods Seventy-eight RP patients and 34 healthy controls were included in this observational study. Anxiety and sleep-quality questionnaires, a complete ophthalmological exam for severity grading and, the collection of salivary samples from participants were assessed for participants. The activity of biomarkers was estimated by ELISA, and statistical analysis was performed to determine associations between the parameters. Associations between underlying psychological factors, grade of disease severity, and biomarkers activity were also examined. Results Fifty-two (67%) of patients had a severe RP, and 26 (33%) had a mild-moderate grade. Fifty-eight (58,9%) patients reported severe levels of anxiety and 18 (23.,1%) a high level. Forty-six (59%) patients obtained pathological values in sleep-quality questionaries and 43 (55.1%) in sleepiness. Patients with RP exhibited significant differences in testosterone, cortisol, sTNFαRII, sIgA and melatonin as compared to controls and patients with a mild-moderate and advanced stage of disease showed greater differences. In covariate analysis, patients with a severe anxiety level also showed greater differences in mean salivary cortisol, sTNFαRII and melatonin and male patients showed lower IgA levels than female. Conclusions The present findings suggest that salivary biomarkers could be suitable non-invasive biochemical markers for the objective assessment of sleep deprivation and anxiety in RP patients. Further research is needed to characterize the effects of untreated negative psychological states and sleep deprivation on increased variability of vision and disease progression, if any.

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“…PRPF8 -mediated RP is a result of ciliary dysfunctioning. [ 69 ] Twenty-two variations have been identified in PRPF8 for RP13, most of which are confined to the terminal exon (Jab1/MPN domain). [ 68 ] These transcripts may escape the non-mediated decay (NMD), which lead to the accumulation of these non-functional variant proteins.…”

Section: Retinitis Pigmentosa1 Genementioning

confidence: 99%

“…And it is possible that misregulation of the circadian rhythms gives rise to retinal diseases by interacting with other environmental factors (bright light, aging, etc). [ 69 ]…”

Section: Retinitis Pigmentosa1 Genementioning

confidence: 99%

Genetic dissection of non-syndromic retinitis pigmentosa

Bhardwaj

Yadav

et al. 2022

Indian J Ophthalmol

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Retinitis pigmentosa (RP) belongs to a group of pigmentary retinopathies. It is the most common form of inherited retinal dystrophy, characterized by progressive degradation of photoreceptors that leads to nyctalopia, and ultimately, complete vision loss. RP is distinguished by the continuous retinal degeneration that progresses from the mid-periphery to the central and peripheral retina. RP was first described and named by Franciscus Cornelius Donders in the year 1857. It is one of the leading causes of bilateral blindness in adults, with an incidence of 1 in 3000 people worldwide. In this review, we are going to focus on the genetic heterogeneity of this disease, which is provided by various inheritance patterns, numerosity of variations and inter-/intra-familial variations based upon penetrance and expressivity. Although over 90 genes have been identified in RP patients, the genetic cause of approximately 50% of RP cases remains unknown. Heterogeneity of RP makes it an extremely complicated ocular impairment. It is so complicated that it is known as “fever of unknown origin”. For prognosis and proper management of the disease, it is necessary to understand its genetic heterogeneity so that each phenotype related to the various genetic variations could be treated.

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

Cited by 6 publications

References 57 publications

Transcriptomic remodeling of the retina in a Zebrafish model of Retinitis Pigmentosa

Transcriptomic remodeling of the retina in a Zebrafish model of Retinitis Pigmentosa

Stress and sleep deprivation-related biomarkers in saliva in patients with retinitis pigmentosa

Genetic dissection of non-syndromic retinitis pigmentosa

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