Abstract
Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium1, account for 10–15% of LCA cases2,3. Whereas previous studies of RPE65 deficiency in both animal models1,4 and patients5,6 attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65−/− mice by generating double– mutant mice with models of pure cone function7 (rhodopsin-deficient mice; Rho−/−) and pure rod function8 (cyclic nucleotide–gated channel α3–deficient mice; Cnga3−/−). The electroretinograms (ERGs) of Rpe65−/− and Rpe65−/−Cnga3−/− mice were almost identical, whereas there was no assessable response in Rpe65−/−Rho−/− mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Redmond, T.M. et al. Rpe65 is necessary for production of 11-cis -vitamin A in the retinal visual cycle. Nature Genet. 20, 344–351 (1998).
Gu, S. et al. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nature Genet. 17, 194–197 (1997).
Marlhens, F. et al. Mutations in RPE65 cause Leber's congenital amaurosis. Nature Genet. 17, 139–141 (1997).
Veske, A., Nilsson, S.E.G., Narfström, K. & Gal, A. Retinal dystrophy of Swedish Briard/Briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57, 57–61 (1999).
Lorenz, B. et al. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest. Ophthalmol. Vis. Sci. 41, 2735–2742 (2000).
Thompson, D.A. et al. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 41, 4293–4299 (2000).
Jaissle, G.B. et al. Evaluation of the rhodopsin knockout mouse as a model of pure cone function. Invest. Ophthalmol. Vis. Sci. 42, 506–513 (2001).
Biel, M. et al. Selective loss of cone function in mice lacking the cyclic nucleotide–gated channel CNG3. Proc. Natl. Acad. Sci. USA 96, 7553–7557 (1999).
Humphries, M.M. et al. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genet. 15, 216–219 (1997).
Hirano, A.A. et al. Cloning and immunocytochemical localization of a cyclic nucleotide–gated channel alpha-subunit to all cone photoreceptors in the mouse retina. J. Comp. Neurol. 421, 80–94 (2000).
Kohl, S. et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature Genet. 19, 257–259 (1998).
Marmor, M. & Zrenner, E. Standard for clinical electroretinography (1994 update). Doc. Ophthalmol. 89, 199–210 (1995).
Fishman, G.A. & Sokol, S. Electrophysiologic Testing (American Academy of Ophthalmology, San Francisco, 1990).
Heckenlively, J.R. & Arden, G.B. in Principles and Practice of Clinical Electrophysiology of Vision (eds. Heckenlively, J.R. & Arden, G.B.) (Mosby-Year Book, St. Louis, 1991).
Van Hooser, J.P. et al. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc. Natl. Acad. Sci. USA 97, 8623–8628 (2000).
Dowling, J.E. Night blindness, dark adaptation, and the electroretinogram. Am. J. Ophthalmol. 50, 875–889 (1960).
Thomas, M.M. & Lamb, T.D. Light adaptation and dark adaptation of human rod photoreceptors measured from the a-wave of the electroretinogram. J. Physiol. 518, 479–496 (1999).
Paupoo, A.A. et al. Human cone photoreceptor responses measured by the electroretinogram a-wave during and after exposure to intense illumination. J. Physiol. 529, 469–482 (2000).
Baylor, D.A., Lamb, T.D. & Yau, K.W. Responses of retinal rods to single photons. J. Physiol. 288, 613–634 (1979).
Connor, J.D. & MacLeod, D.I. Rod photoreceptors detect rapid flicker. Science 195, 698–699 (1977).
Sadowski, B. & Zrenner, E. Differential diagnosis of cone dystrophies. Ophthalmologe 91, 719–729 (1994).
Cideciyan, A.V. et al. Rod and cone visual cycle consequences of a null mutation in the 11- cis -retinol dehydrogenase gene in man. Vis. Neurosci. 17, 667–678 (2000).
Nakamura, M., Hotta, Y., Tanikawa, A., Terasaki, H. & Miyake, Y. A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene. Invest. Ophthalmol. Vis. Sci. 41, 3925–3932 (2000).
Acland, G.M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nature Genet. 28, 92–95 (2001).
Wenzel, A. et al. c-fos controls the “private pathway” of light-induced apoptosis of retinal photoreceptors. J. Neurosci. 20, 81–88 (2000).
Redmond, T.M. & Hamel, C.P. Genetic analysis of RPE65: from human disease to mouse model. Methods Enzymol. 316, 705–724 (2000).
Acknowledgements
We thank K. Mai and D. Greuter for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (grants SFB 430 C2, Se837/1-1 and Re318/2-1), the Swiss National Science Foundation, the Velux Foundation, Glarus, Switzerland and the Fortüne program of the University of Tübingen (grant number 845).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Seeliger, M., Grimm, C., Ståhlberg, F. et al. New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. Nat Genet 29, 70–74 (2001). https://doi.org/10.1038/ng712
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng712
This article is cited by
-
Changes in morphology and visual function over time in mouse models of retinal degeneration: an SD-OCT, histology, and electroretinography study
Japanese Journal of Ophthalmology (2016)
-
A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa
Nature Communications (2015)
-
Electroretinographic assessment of rod- and cone-mediated bipolar cell pathways using flicker stimuli in mice
Scientific Reports (2015)
-
RPE65 gene therapy slows cone loss in Rpe65-deficient dogs
Gene Therapy (2013)
-
Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity
Documenta Ophthalmologica (2013)