Stem Cells as Tools for Studying the Genetics of Inherited Retinal Degenerations

Wiley, Luke A; Burnight, Erin R; Mullins, Robert F.; Stone, Edwin M.; Tucker, Budd A.

doi:10.1101/cshperspect.a017160

Cited by 12 publications

(10 citation statements)

References 61 publications

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“…Future studies are needed to determine if this plasticity can be elicited outside of early development and if it occurs in human patients with retinal degenerative diseases. In addition, it remains to be investigated how plasticity can be reactivated to optimally integrate newly generated signals (e.g., optogenetics; Busskamp et al, 2012 ) and neurons (e.g., generated from stem cells; Wiley et al, 2015 ) into circuits in vision restoration strategies.…”

Section: Discussionmentioning

confidence: 99%

Synaptic remodeling of neuronal circuits in early retinal degeneration

Soto

Kerschensteiner

2015

Front. Cell. Neurosci.

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Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies.

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Section: Discussionmentioning

confidence: 99%

Synaptic remodeling of neuronal circuits in early retinal degeneration

Soto

Kerschensteiner

2015

Front. Cell. Neurosci.

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“…For example, to determine whether a variant has an effect on EYS pre‐mRNA splicing, one ideally would make use of patient‐derived cells, by extracting RNA and study EYS mRNA composition and levels. Given the retina‐specific expression of EYS , one would have to make use of induced pluripotent stem cell (iPSC) technology, that is, reprogram somatic cells to pluripotency, and differentiate the iPSC cells into retinal cells (Wiley, Burnight, Mullins, Stone, & Tucker, ). This is however very labor intensive and time consuming.…”

Section: Future Directionsmentioning

confidence: 99%

EYSmutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa

et al. 2017

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Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www.LOVD.nl/EYS). We also describe 36 additional index cases, carrying 26 novel variants. Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. Classification of all variants using the American College of Medical Genetics and Genomics guidelines revealed that the predicted pathogenicity of these variants cover the complete spectrum ranging from likely benign to pathogenic, although especially missense variants largely fall in the category of uncertain significance. Besides the identification of likely benign alleles previously reported as being probably pathogenic, our comprehensive analysis underscores the need of functional assays to assess the causality of EYS variants, in order to improve molecular diagnostics and counseling of patients with EYS-associated RP.

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“…The remainder of the present review focuses on the utility of iPSCs for investigation of disease pathophysiology. In-depth reviews of the other medical applications of iPSCs have recently been published [10][11][12].…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Concise Review: Patient-Specific Stem Cells to Interrogate Inherited Eye Disease

Giacalone

Wiley

Burnight

et al. 2015

Stem Cells Translational Medicine

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Heritable diseases of the retina are major causes of blindness worldwide. The recent success of gene augmentation trials for the treatment of RPE65-associated Leber congenital amaurosis has underscored the need for model systems that accurately recapitulate disease. How induced pluripotent stem cell technology is being used to confirm the pathogenesis of novel genetic variants, interrogate the pathophysiology of disease, and accelerate the development of patient-centered treatments is discussed.

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Stem Cells as Tools for Studying the Genetics of Inherited Retinal Degenerations

Cited by 12 publications

References 61 publications

Synaptic remodeling of neuronal circuits in early retinal degeneration

Synaptic remodeling of neuronal circuits in early retinal degeneration

EYSmutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa

Concise Review: Patient-Specific Stem Cells to Interrogate Inherited Eye Disease

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