Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction

Haider, Neena B.; Mollema, Nissa; Gaule, Meghan; Yuan, Ye; Sachs, Andrew J.; Nystuen, Arne; Naggert, Jürgen Κ.; Nishina, Patsy M.

doi:10.1016/j.exer.2009.04.006

Cited by 72 publications

(87 citation statements)

References 33 publications

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“…This positive feedback might elevate NRL expression to a threshold, or sustain expression at a threshold, that biases the precursor cell to a rod fate. The second action of NRL is the induction of NR2E3 (9, 10), which promotes the activation of downstream rod genes and suppression of cone genes (11)(12)(13)(14)(15). On the basis of the developmental expression patterns of ROR␤1 and ROR␤2, it is possible that, in early differentiating rods, NRL is induced by ROR␤1 and, in the later expanding rod population, by both ROR␤ isoforms because ROR␤2 is induced by NRL in the neonatal phase.…”

Section: Mutual Activation Of Rorb and Nrl Genes In Rodmentioning

confidence: 99%

Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor β by the Rod Transcription Factor NRL

Liu

et al. 2014

Journal of Biological Chemistry

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Background:The orphan receptor isoforms ROR␤1 and ROR␤2 encoded by Rorb are differentially expressed during retinal differentiation. Results: The ROR␤2 isoform is photoreceptor-specific and induces the rod differentiation factor NRL, which, in turn, induces ROR␤2 through positive feedback. Conclusion: NRL induces the ROR␤2-specific promoter of Rorb, its own inducer gene. Significance: Positive feedback between Nrl and Rorb genes reinforces the commitment to a rod differentiation fate.

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Section: Mutual Activation Of Rorb and Nrl Genes In Rodmentioning

confidence: 99%

Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor β by the Rod Transcription Factor NRL

Liu

et al. 2014

Journal of Biological Chemistry

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“…22 Before the present work, the diagnoses of patients, such as ESCS, Goldmann-Favre syndrome, clumped pigmentary retinopathy, and retinitis pigmentosa, have usually been listed as the human disease expressions comparable to the mouse model. 16,17,49 Based on the results of this study, more specific comparisons about disease progression can now be made between rd7 mice and patients with NR2E3 mutations. Already noted as a difference between rd7 and human patients is that young rd7 mice have rod ERG function and normal (not hypernormal) S-cone ERGs, although how long these signals persist is debated.…”

Section: Approaching a Clinical Trial For Patients With Nr2e3 Mutationsmentioning

confidence: 99%

Cone Vision Changes in the Enhanced S-Cone Syndrome Caused byNR2E3Gene Mutations

Garafalo

Calzetti

Cideciyan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine the progression of cone vision loss in patients with recessive disease from NR2E3 gene mutations. METHODS.Patients with NR2E3 mutations (n ¼ 37) were studied as a retrospective observational case series clinically and with chromatic static perimetry. Patients were investigated cross-sectionally, and a subset was followed longitudinally. RESULTS.Patients showed a range of visual acuities; there was no clear relationship to age. With kinetic perimetry (V4e target), a full field could be retained over many years. Other patients showed progression from a full field, with or without pericentral scotomas, to a small central island. Three patterns of S-cone function were defined, based on percentage of hypersensitive S-cone loci in the field. From occupying most of the visual field, hyperfunctioning S-cone loci could diminish in percent, remaining largely in the periphery. Normal S-cone functioning then dominates, followed by the appearance of an annular region of abnormal S-cone loci approximately 108 to 408 from the fovea. Overall, S-cone sensitivity declined 2.6 times faster than L/M-cone sensitivity.CONCLUSIONS. Murine proof-of-concept studies suggest that clinical trials of patients with NR2E3 mutations may be forthcoming. Patterns of S-cone hyperfunction across the field would serve as a means to categorize patients as entry criteria or cohort selection in clinical trials. S-cone perimetry can be measured in the clinic and would be the logical efficacy monitor for therapeutic strategies. Given further understanding of the natural history of the disease, targeting the annular region of S-cone dysfunction for a focal therapy or for monitoring in a retina-wide intervention warrants consideration.

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“…Therefore, loss of NR2E3 results in retinas with a decreased number of rod photoreceptors but an increase in cones, predominantly expressing the S-cone opsin resulting in ESCS. 11,12 …”

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confidence: 99%

Expanded Clinical Spectrum of Enhanced S-Cone Syndrome

et al. 2013

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nhanced S-cone syndrome (ESCS) is a rare, autosomal recessive inherited retinal dystrophy first described more than 2 decades ago. [1][2][3] Because of the variable clinical presentation, it is not unusual that patients with ESCS are misdiagnosed as having atypical retinitis pigmentosa, congenital stationary night blindness, or X-linked retinoschisis.The adult human retina typically consists of approximately 120 million rods and 6 million cones containing 3 cone subtypes: short-wavelength (S), medium-wavelength (M), and long-wavelength (L) cones. S-cones are the minority (about 10%) 4 subset of cones in healthy human retinas w h e r e a s i n E S C S , S -c o n e s a r e t h e m a j o r i t y c o n e subtype. [1][2][3]5,6 Electroretinography (ERG) and psychophysical testing play a key role in diagnosing patients with ESCS.Characteristic ERG findings are the presence of similar waveforms in the maximum dark-adapted response and singleflash light-adapted waveform. An associated ERG feature is disproportionately reduced 30-Hz cone flicker to the singleflash cone amplitude. [7][8][9] The basis of these waveforms has been explored. 10 All of these findings occur in the absence of rod function. [1][2][3]7,8 S-cone stimuli can show supernormal responses, although the relative increase in S-cone function compared with L-and M-cone function is diagnostic and independent of degree of disease severity. Psychophysical testing demonstrating the abnormal ratio of S-cone to L-and M-cone function was especially helpful in proving that ESCS and the more severe expression Goldmann-Favre syndrome were part of the same disease spectrum. 3 IMPORTANCE New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy. OBJECTIVE To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene. DESIGN Retrospective, noncomparative case series of 31 patients examined between 1983 and 2012. SETTING Academic and private ophthalmology practices specialized in retinal dystrophies. PARTICIPANTS A cohort of patients diagnosed with ESCS and harboring known NR2E3 mutations. INTERVENTION Patients had ophthalmic examinations including visual function testing that led to the original diagnosis. MAIN OUTCOMES AND MEASURES New fundus features captured with imaging modalities. RESULTS New clinical observations in ESCS include (1) torpedo-like, deep atrophic lesions with a small hyperpigmented rim, variably sized and predominantly located along the arcades; (2) circumferential fibrotic scars in the posterior pole with a spared center and large fibrotic scars around the optic nerve head; and (3) yellow dots in areas of relatively normal-appearing retina.CONCLUSIONS AND RELEVANCE Enhanced S-cone syndrome has more pleiotropy than previously appreciated. While the nummular type of pigmentation at the level of the retinal pigment epithelium and cystoid or schisis-like maculopathy with typical functional findings remain classic hallmarks of the disease, changes...

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Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction

Cited by 72 publications

References 33 publications

Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor β by the Rod Transcription Factor NRL

Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor β by the Rod Transcription Factor NRL

Cone Vision Changes in the Enhanced S-Cone Syndrome Caused byNR2E3Gene Mutations

Expanded Clinical Spectrum of Enhanced S-Cone Syndrome

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