RDH5 -Related Fundus Albipunctatus in a Large Japanese Cohort

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Abstract

Purpose

To investigate clinical characteristics of RDH5-related fundus albipunctatus (FAP) in a Japanese cohort.

Methods

Twenty-five patients from 22 pedigrees with RDH5-related FAP were studied. Ophthalmic medical records were reviewed. For genetic analysis, either Sanger sequencing of the RDH5 gene or whole-exome sequencing was performed.

Results

Genetic analysis identified eight different RDH5 variants, including seven known RDH5 variants (p.G35S, p.G107R, p.R167H, p.A240GfsX19, p.R278X, p.R280H, and p.L310delinsEV) and a novel variant: c.259C>T (p.Q87X). The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles). Of 50 eyes examined, 44 eyes (88.0%) showed logMAR best-corrected visual acuity (BCVA) of 0.10 or better. In optical coherence tomography, macular involvement was observed in 12 patients (24 eyes). Ten patients (83.3%) who had good BCVA (0.10 or better) exhibited diffuse disruption of the outer retina with foveal sparing, and two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA. Among the 24 eyes, ring-or crescent-shaped hyperautofluorescence or irregular autofluorescence around the fovea was observed in 15 eyes (83.3%) of 18 eyes examined by fundus autofluorescence imaging. Full-field electroretinography showed extinguished or severely decreased rod responses in all 23 examined patients, whereas decreased cone responses were seen in 17 patients (73.9%).

Conclusions

Multimodal imaging and electroretinography of RDH5-related FAP revealed high frequencies of macular involvement in older patients and decreased cone responses. Our findings suggest that progressive macular/cone dysfunction, as well as delayed rod function, may be key phenotypic features of RDH5-related FAP.

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Most cited references 48

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The cone-specific visual cycle.

Jin-Shan Wang, Vladimir J. Kefalov (2011)

Cone photoreceptors mediate our daytime vision and function under bright and rapidly-changing light conditions. As their visual pigment is destroyed in the process of photoactivation, the continuous function of cones imposes the need for rapid recycling of their chromophore and regeneration of their pigment. The canonical retinoid visual cycle through the retinal pigment epithelium cells recycles chromophore and supplies it to both rods and cones. However, shortcomings of this pathway, including its slow rate and competition with rods for chromophore, have led to the suggestion that cones might use a separate mechanism for recycling of chromophore. In the past four decades biochemical studies have identified enzymatic activities consistent with recycling chromophore in the retinas of cone-dominant animals, such as chicken and ground squirrel. These studies have led to the hypothesis of a cone-specific retina visual cycle. The physiological relevance of these studies was controversial for a long time and evidence for the function of this visual cycle emerged only in very recent studies and will be the focus of this review. The retina visual cycle supplies chromophore and promotes pigment regeneration only in cones but not in rods. This pathway is independent of the pigment epithelium and instead involves the Müller cells in the retina, where chromophore is recycled and supplied selectively to cones. The rapid supply of chromophore through the retina visual cycle is critical for extending the dynamic range of cones to bright light and for their rapid dark adaptation following exposure to light. The importance of the retina visual cycle is emphasized also by its preservation through evolution as its function has now been demonstrated in species ranging from salamander to zebrafish, mouse, primate, and human. Copyright © 2010 Elsevier Ltd. All rights reserved.

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Isomerization and oxidation of vitamin a in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight.

David Clemmons, Gabriel Travis, A. Corso-Radu … (2002)

The first step toward light perception is 11-cis to all-trans photoisomerization of the retinaldehyde chromophore in a rod or cone opsin-pigment molecule. Light sensitivity of the opsin pigment is restored through a multistep pathway called the visual cycle, which effects all-trans to 11-cis re-isomerization of the retinoid chromophore. The maximum throughput of the known visual cycle, however, is too slow to explain sustained photosensitivity in bright light. Here, we demonstrate three novel enzymatic activities in cone-dominant ground-squirrel and chicken retinas: an all-trans-retinol isomerase, an 11-cis-retinyl-ester synthase, and an 11-cis-retinol dehydrogenase. Together these activities comprise a novel pathway that regenerates opsin photopigments at a rate 20-fold faster than the known visual cycle. We suggest that this pathway is responsible for sustained daylight vision in vertebrates.

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Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

Hiroyuki Yamamoto, András Simon, Ulf Eriksson … (1999)

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.

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Author and article information

Journal

Journal ID (nlm-ta): Invest Ophthalmol Vis Sci

Journal ID (iso-abbrev): Invest. Ophthalmol. Vis. Sci

Journal ID (pmc): iovs

Journal ID (publisher-id): IOVS

Title: Investigative Ophthalmology & Visual Science

Publisher: The Association for Research in Vision and Ophthalmology

ISSN (Print): 0146-0404

ISSN (Electronic): 1552-5783

Publication date (Electronic): 30 March 2020

Publication date Collection: March 2020

Volume: 61

Issue: 3

Electronic Location Identifier: 53

Affiliations

[1 ] Department of Ophthalmology, The Jikei University School of Medicine , Tokyo, Japan

[2 ] Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine , Tokyo, Japan

[3 ] Department of Ophthalmology, Nagoya University Graduate School of Medicine , Aichi, Japan

[4 ] Department of Ophthalmology, Kindai University Faculty of Medicine , Osaka, Japan

[5 ] Department of Ophthalmology, Mie University Graduate School of Medicine , Mie, Japan

[6 ] Laboratory of Visual Physiology, Division of Vision Research, National Hospital Organization Tokyo Medical Center , Tokyo, Japan

[7 ] Department of Laboratory Medicine, The Jikei University School of Medicine , Tokyo, Japan

[8 ] Department of Ophthalmology, University of Occupational and Environmental Health , Kitakyushu, Japan

[9 ] Division of Molecular and Cellular Biology, National Institute of Sensory Organs , National Hospital Organization Tokyo Medical Center, Tokyo, Japan

Author notes

Corresponding author: Takaaki Hayashi, Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan; taka@ 123456jikei.ac.jp .

Article

Publisher ID: IOVS-19-27599

DOI: 10.1167/iovs.61.3.53

PMC ID: 7401827

PubMed ID: 32232344

SO-VID: c5e1f70b-2788-4dc6-8955-6bf6d8a31a59

License:

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

History

Date accepted : 29 January 2020

Date received : 28 May 2019

Page count

Pages: 11

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RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort

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Most cited references 48

The cone-specific visual cycle.

Isomerization and oxidation of vitamin a in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight.

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

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