Abstract:Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH… Show more
“…Retinal histologic study of Rdh12 −/− animal models has shown shortened photoreceptors that have a reduced capacity for retinoid processing, 37 , 38 and enlarged phagosomes in the RPE. 39 The latter has been associated with suboptimal RPE phagocytosis of photoreceptor outer segments, causing toxicity and subsequent cell death. 40 , 41 …”
Purpose
RDH12
is among the most common genes found in individuals with early-onset severe retinal (EOSRD). Adaptive optics scanning light ophthalmoscopy (AOSLO) enables resolution of individual rod and cone photoreceptors in the retina. This study presents the first AOSLO imaging of individuals with
RDH12
-associated EOSRD.
Methods
Case series of patients who attended Moorfields Eye Hospital (London, UK). Spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and blue autofluorescence imaging were analyzed. En face image sequences of photoreceptors were recorded using either of two AOSLO modalities. Cross-sectional analysis was undertaken for seven patients and longitudinal analysis for one patient.
Results
Nine eyes from eight patients are presented in this case series. The mean age at the time of the assessment was 11.2 ± 6.5 years of age (range 7–29). A subfoveal continuous ellipsoid zone (EZ) line was present in eight eyes. Posterior pole AOSLO revealed patches of cone mosaics. Average cone densities at regions of interest 0.5° to the fovea ranged from 12,620 to 23,660 cells/mm
2
, whereas intercell spacing ranged from 7.0 to 9.7 µm.
Conclusions
This study demonstrates that AOSLO can provide useful high-quality images in patients with EOSRD, even during childhood, with nystagmus, and early macular atrophy. Cones at the posterior pole can appear as scattered islands or, possibly later in life, as a single subfoveal conglomerate. Detailed image analysis suggests that retinal pigment epithelial stress and dysfunction may be the initial step toward degeneration, with NIR being a useful tool to assess retinal well-being in
RDH12
-associated EOSRD.
“…Retinal histologic study of Rdh12 −/− animal models has shown shortened photoreceptors that have a reduced capacity for retinoid processing, 37 , 38 and enlarged phagosomes in the RPE. 39 The latter has been associated with suboptimal RPE phagocytosis of photoreceptor outer segments, causing toxicity and subsequent cell death. 40 , 41 …”
Purpose
RDH12
is among the most common genes found in individuals with early-onset severe retinal (EOSRD). Adaptive optics scanning light ophthalmoscopy (AOSLO) enables resolution of individual rod and cone photoreceptors in the retina. This study presents the first AOSLO imaging of individuals with
RDH12
-associated EOSRD.
Methods
Case series of patients who attended Moorfields Eye Hospital (London, UK). Spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and blue autofluorescence imaging were analyzed. En face image sequences of photoreceptors were recorded using either of two AOSLO modalities. Cross-sectional analysis was undertaken for seven patients and longitudinal analysis for one patient.
Results
Nine eyes from eight patients are presented in this case series. The mean age at the time of the assessment was 11.2 ± 6.5 years of age (range 7–29). A subfoveal continuous ellipsoid zone (EZ) line was present in eight eyes. Posterior pole AOSLO revealed patches of cone mosaics. Average cone densities at regions of interest 0.5° to the fovea ranged from 12,620 to 23,660 cells/mm
2
, whereas intercell spacing ranged from 7.0 to 9.7 µm.
Conclusions
This study demonstrates that AOSLO can provide useful high-quality images in patients with EOSRD, even during childhood, with nystagmus, and early macular atrophy. Cones at the posterior pole can appear as scattered islands or, possibly later in life, as a single subfoveal conglomerate. Detailed image analysis suggests that retinal pigment epithelial stress and dysfunction may be the initial step toward degeneration, with NIR being a useful tool to assess retinal well-being in
RDH12
-associated EOSRD.
“…To determine the optimum dosing concentrations, cells were treated with various concentrations of NACA and taurine for 24 h and the cell viability was assessed using MTT assay. TUDCA concentration was based on a previous publication [ 12 ]. For dosing experiments, cells were plated in 6-well plates at a seeding density of 600,000 cells per well.…”
Section: Methodsmentioning
confidence: 99%
“…Samples were analysed using western blot, as previously described [ 12 ], using anti-BIP (1:1000; Abcam ab21685, Cambridge, UK) overnight at 4 °C. The membrane was stripped and re-probed with anti-β-actin for 2 h at room temperature (1:5000; Sigma A2228).…”
Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy, affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, with no approved therapy. CHM is caused by mutations in the CHM gene, which encodes the ubiquitously expressed Rab escort protein 1 (REP1). REP1 is involved in prenylation, a post-translational modification of Rab proteins, and plays an essential role in intracellular trafficking. In this study, we examined oxidative and endoplasmic reticulum (ER) stress pathways in chmru848 zebrafish and CHMY42X patient fibroblasts, and screened a number of neuroprotectants for their ability to reduce stress. The expression of the oxidative stress markers txn, cat and sod3a, and the ER stress markers bip, atf4 and atf6, were dysregulated in chmru848 fish. The expression of SOD2 was also reduced in CHMY42X fibroblasts, along with reduced BIP and increased CHOP expression. The lack of REP1 is associated with defects in vesicular trafficking, photoreceptor outer segment phagocytosis and melanosome transport, leading to increased levels of stress within the retina and RPE. Drugs targeting oxidative and ER stress pathways represent novel therapeutic avenues.
“…also suggested that RDH12 may regulate the flow of retinoids in the eye, playing an important part against light-induced photoreceptor apoptosis during persistent illumination ( 21 ). Recently, RDH12 metabolizing all-trans retinal has likewise been found to be key in protecting cells from oxidative and endoplasmic reticulum (ER) stress ( 22 ). Figure 1.…”
Retinol dehydrogenase 12 (RDH12) is a small gene located on chromosome 14, encoding an enzyme capable of metabolizing retinoids. It is primarily located in photoreceptor inner segments and thereby is believed to have an important role in clearing excessive retinal and other toxic aldehydes produced by light exposure. Clinical features: RDH12-associated retinopathy has wide phenotypic variability; including early-onset severe retinal dystrophy/Leber Congenital Amaurosis (EOSRD/LCA; most frequent presentation), retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. It can be inherited in an autosomal recessive and dominant fashion. RDH12-EOSRD/LCA’s key features are early visual impairment, petal-shaped, coloboma-like macular atrophy with variegated watercolour-like pattern, peripapillary sparing, and often dense bone spicule pigmentation. Future directions: There is currently no treatment available for RDH12-retinopathy. However, extensive preclinical investigations and an ongoing prospective natural history study are preparing the necessary foundation to design and establish forthcoming clinical trials. Herein, we will concisely review pathophysiology, molecular genetics, clinical features, and discuss therapeutic approaches.
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