Retinol dehydrogenase 12 (RDH12): Role in vision, retinal disease and future perspectives

Sarkar, Hajrah; Moosajee, Mariya

doi:10.1016/j.exer.2019.107793

Cited by 22 publications

(14 citation statements)

References 40 publications

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“…41,42 Further oxidation is required to restore 11-cis retinal, which is then catalyzed by retinol dehydrogenases, distributed in the retina and RPE in a number of isoforms with overlapping activities. 39,43,44 Another function of RPE is phagocytosis. Photoreceptor cells continuously generate new outer segments from their base while simultaneously releasing outer segments to be phagocytosed by the RPE monolayer.…”

Section: Discussionmentioning

confidence: 99%

Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction

Lin

McLelland

Aramant

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To study if human embryonic stem cell-derived photoreceptors could survive and function without the support of retinal pigment epithelium (RPE) after transplantation into Royal College of Surgeons rats, a rat model of retinal degeneration caused by RPE dysfunction. METHODS. CSC14 human embryonic stem cells were differentiated into primordial eye structures called retinal organoids. Retinal organoids were analyzed by quantitative PCR and immunofluorescence and compared with human fetal retina. Retinal organoid sheets (30-70 day of differentiation) were transplanted into immunodeficient RCS rats, aged 44 to 56 days. The development of transplant organoids in vivo in relation to the host was examined by optical coherence tomography. Visual function was assessed by optokinetic testing, electroretinogram, and superior colliculus electrophysiologic recording. Cryostat sections were analyzed for various retinal, synaptic, and donor markers. RESULTS. Retinal organoids showed similar gene expression to human fetal retina transplanted rats demonstrated significant improvement in visual function compared with RCS nonsurgery and sham surgery controls by ERGs at 2 months after surgery (but not later), optokinetic testing (up to 6 months after surgery) and electrophysiologic superior colliculus recordings (6-8 months after surgery). The transplanted organoids survived more than 7 months; developed photoreceptors with inner and outer segments, and other retinal cells; and were well-integrated within the host. CONCLUSIONS. This study, to our knowledge, is the first to show that transplanted photoreceptors survive and function even with host's dysfunctional RPE. Our findings suggest that transplantation of organoid sheets from stem cells may be a promising approach/therapeutic for blinding diseases.

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Section: Discussionmentioning

confidence: 99%

Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction

Lin

McLelland

Aramant

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…This gene encodes the retinol dehydrogenase 12 (RDH12), which is expressed predominantly in the inner segment of photoreceptors, where plays catalyzing the reduction of all‐trans retinal to all‐trans retinol. As reviewed by Sarkar and Moosajee (2019), some studies suggest that RDH12 protects the retina from excessive illumination by counteracting accumulation of all‐trans‐retinal or avoiding a build‐up of toxic lipid peroxidation products in the photoreceptor.…”

Section: Resultsmentioning

confidence: 99%

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Sallum

Motta

Arno

et al. 2020

American J of Med Genetics Pt C

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Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion. K E Y W O R D S causal genes, childhood blindness, early-onset retinal dystrophy (EORD), genotypephenotype, Leber congenital amaurosis (LCA), pathogenic variants 1 | INTRODUCTION Leber congenital amaurosis (LCA) is the most severe and earliest onset inherited retinal dystrophy. Affected individuals usually present, in the first year of life with severe visual impairment, nystagmus and occasionally a systemic manifestation (Francis, 2006). Phenotypic variability in fundus abnormality, refractive errors, photophobia or lightseeking behavior, nyctalopia, nystagmus, low visual acuity, and Franceschetti's oculo-digital sign, are also commonly observed in these patients (Chung & Traboulsi, 2009; den Hollander, Roepman, Koenekoop, & Cremers, 2008). Early-onset retinal dystrophy (EORD) can be considered as belonging to the same LCA spectrum but a milder form, where signs and symptoms appear after the first year of life up to 5-7 years-old (Weleber, Francis, Trzupek, & Beattie, 2004), but still a disease that severely compromises vision. Clinically, LCA and EORD are similar and may represent a continuum; the distinction between them is an extinguished or markedly diminished ERG response before the first year of life for individuals with

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“…RDH12 is an NADPH-dependent retinal reductase, expressed in the inner segments of photoreceptors. Loss of functional RDH12 is thought to result in build-up of toxic retinoids, although the exact disease mechanisms are not yet fully understood ( Sarkar and Moosajee, 2019 ). Induced pluripotent stem cells (iPSCs) provide a useful resource to investigate inherited retinal dystrophies in cell types that would otherwise be inaccessible for study.…”

Section: Resource Detailsmentioning

confidence: 99%

Generation of two human iPSC lines from patients with autosomal dominant retinitis pigmentosa (UCLi014-A) and autosomal recessive Leber congenital amaurosis (UCLi015-A), associated with RDH12 variants

Sarkar

Méjécase

Harding³

et al. 2021

Stem Cell Research

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Induced pluripotent stem cell (iPSC) lines were generated from two patients with RDH12 variants. UCLi014-A is from a patient with heterozygous frameshift mutation c.759del p.(Phe254Leufs*24), associated with autosomal dominant retinitis pigmentosa. UCLi015-A is from a patient with homozygous missense mutation c.619A > G p.(Asn207Asp), associated with Leber congenital amaurosis. Fibroblasts were derived from skin biopsies and reprogrammed using integration free episomal reprogramming plasmids. The iPSC lines expressed pluripotency markers, exhibited differentiation potential in vitro and displayed normal karyotypes. These cell lines will act as a tool for disease modelling, enabling comparison of disease mechanisms, identification of therapeutic targets and drug screening.

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Retinol dehydrogenase 12 (RDH12): Role in vision, retinal disease and future perspectives

Abstract: Retinol dehydrogenase 12 (RDH12) structure, function and role in vision. • Disease mechanisms and clinical phenotype of RDH12 retinopathies. • Therapeutic avenues and consideration for future research.

Cited by 22 publications

References 40 publications

Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction

Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Generation of two human iPSC lines from patients with autosomal dominant retinitis pigmentosa (UCLi014-A) and autosomal recessive Leber congenital amaurosis (UCLi015-A), associated with RDH12 variants

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