Original article
Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture☆

This lecture was presented at the Annual Meeting of the American Academy of Ophthalmology, October 22, 2000.
https://doi.org/10.1016/S0002-9394(00)00737-6Get rights and content

Abstract

PURPOSE: To compare the clinical findings of the various forms of stationary night blindness caused by mutations in identified genes encoding proteins of photoreceptors or the retinal pigment epithelium.

METHODS: Review of the visual acuities, visual fields, fundi, dark-adaptation curves, and electroretinograms from patients with stationary night blindness caused by mutations in the genes RHO, GNAT1, PDE6B, RHOK, SAG, RDH5, and CACNA1F, respectively encoding rhodopsin, the α subunit of rod transducin, the β subunit of rod cGMP-phosphodiesterase, rhodopsin kinase, arrestin, 11-cis retinol dehydrogenase, and a retinal L-type calcium channel.

RESULTS: In the evaluated forms of stationary night blindness, the time course of dark adaptation and the characteristics of the electroretinogram indicate that rod photoreceptors are present and that they function, although abnormally. In night blindness resulting from defects in rhodopsin, the α subunit of rod transducin, or the β subunit of rod cGMP phosphodiesterase, rod photoreceptors respond only to light intensities far brighter than normal, and the sensitivity of rods to light is similar to that of normal individuals who are not dark adapted. In fundus albipunctatus and in Oguchi disease, the rod photoreceptors can achieve normal sensitivity to dim light but only after 2 or more hours of dark adaptation, compared with approximately 0.5 hours for normal individuals. In each of these forms of stationary night blindness, the poor rod sensitivity and the time course of dark adaptation correlate with the known or presumed physiologic abnormalities caused by the identified gene defects. Patients with some forms of stationary night blindness, such as fundus albipunctatus and Oguchi disease, may develop degeneration of the retina leading to severe loss of vision in later life.

CONCLUSIONS: The identification of the mutant genes causing forms of stationary night blindness refines the classification of these diseases and enhances our understanding of the underlying physiologic defects. Ophthalmologists must be aware that although these diseases are traditionally categorized as “stationary,” some of them lead to reduced visual acuity or constricted visual fields, especially in older patients. Efforts to develop therapies for these diseases should concentrate on these more severe forms.

Section snippets

Diagnosis of night blindness

A century ago, night-blind individuals were handicapped at night. They hurried home at the approach of dusk, and, if caught outside at night, they walked with “head erect, arms extended, and hands open.”2 The situation is very different today. With ubiquitous electric illumination, we are able to see in color (that is, we use our cones) throughout the night; rods are no longer essential for many nighttime activities. Patients with night blindness may not complain of their condition. They may

The dark-adaptation curve

After exposure to bright light for a time sufficient to bleach 25% or more of the rhodopsin in the retina, normal rods are insensitive to light and cones respond only to very bright stimuli. A subject’s subsequent recovery of light sensitivity can be monitored by placing the subject in the dark and periodically presenting spots of light of varying intensity in the visual field and asking the subject if they are perceptible. A plot of the light intensity of a minimally perceptible spot versus

Electroretinography

Standard electroretinograms are performed in patients with pharmacologically dilated pupils and after full dark adaptation of the retina (that is, approximately 30 to 40 minutes). The electroretinogram is measured noninvasively with a contact lens electrode placed on the cornea, and it is recorded with corneal voltage on the y axis and time on the x axis. The response to a brief (usually less than 0.1 ms) flash of light (Figure 2) is divided into components or “waves.” The a-wave is a fast,

The phototransduction cascade

In response to photons of visible light, a chain of chemical reactions occurs in photoreceptor cells. Scientists have identified many and perhaps most of the proteins involved in this biochemical pathway, called the phototransduction cascade. Rods and cones have similar phototransduction pathways with the protein components being similar but encoded by distinct genes. The chemical reactions that initiate our sense of vision in dim light take place in the outer segments of the rod

Rhodopsin and dominant stationary night blindness

The first mutations identified as causes of stationary night blindness were found in the rhodopsin gene.18, 19, 20 In the dark-adapted state, the protein component of rhodopsin, called opsin, is covalently linked to the chromophore 11-cis-retinal, a derivative of vitamin A. A photon of light interacts with the chromophore, changing its conformation to all-trans; this in turn induces conformational changes in rhodopsin that activate it (Figure 3).

Three different dominant mutations in the

The alpha subunit of rod transducin and the nougaret form of stationary night blindness

Transducin is the protein that mediates the second step in the phototransduction cascade (Figure 3). Photoactivated rhodopsin molecules interact with and activate the α subunit of transducin. There has been only one disease-causing mutation found so far in the gene encoding the α subunit of transducin, and it was found in a single, large family described below. The mutation changes an amino acid in the encoded protein: a glycine at position 38 changes to aspartic acid (Gly38Asp).74

In 1838 Cunier

The beta subunit of rod cGMP-phosphodiesterase and the rambusch form of stationary night blindness

Rod cGMP-phosphodiesterase is the third member of the rod phototransduction cascade (Figure 3). This enzyme is composed of four main subunits: one α subunit, one β subunit, and two γ subunits: During phototransduction in normal retinas, phosphodiesterase is activated by transducin, at which point it rapidly hydrolyzes cGMP in the cytoplasm. The reduction in the concentration of cGMP causes channels on the plasma membrane to close, thereby hyperpolarizing the rod outer segment. This

Rhodopsin kinase, arrestin, and Oguchi disease

Rhodopsin kinase and arrestin act in sequence to deactivate rhodopsin to stop the phototransduction cascade (Figure 3). Rhodopsin kinase recognizes photoactivated rhodopsin and phosphorylates serine and threonine residues near rhodopsin’s carboxy terminus.32, 33 Arrestin forms a complex with phosphorylated rhodopsin, and this complex prevents further interaction of the activated rhodopsin with transducin. Mutations in either the rhodopsin kinase gene or the arrestin gene cause a recessive form

11-cis retinol dehydrogenase (11-cis rdh) and fundus albipunctatus

The five proteins discussed above are all found in rod photoreceptors and participate in the rod phototransduction cascade; 11-cis RDH is found instead in the retinal pigment epithelium. It is a key enzyme necessary for the production of 11-cis retinal, which is then transported to the neighboring photoreceptors for use as the chromophore in rhodopsin and in the cone opsins (Figure 3). Mutations in the gene encoding 11-cis RDH cause a distinct form of stationary night blindness called fundus

A retinal L-type calcium channel and the incomplete form of X-linked stationary night blindness

Two forms of X-linked stationary night blindness exist that were originally distinguished by differences in electroretinograms.10 The electroretinograms of both forms have intact rod a-waves and diminished rod b-waves, and thus both are of the Schubert-Bornschein type. However, in one, called the incomplete type, a subnormal rod b-wave is clearly evident, whereas in the other, called the complete type, the rod b-wave is absent under all test conditions.10 The X-linked incomplete and complete

Conclusion

The identification of genes causing some forms of stationary night blindness in the last 8 years has greatly increased our understanding of this group of diseases. We have learned that rod photoreceptors are alive and functioning, although abnormally, in the forms of night blindness with identified gene defects. In some types of the disease, such as fundus albipunctatus, cones are abnormally functioning as well. Finally, some forms of “stationary” night blindness are associated with reduced

Acknowledgements

I thank Drs Eliot L. Berson, Michael A. Sandberg, Yozo Miyake, Mitsuru Nakazawa, Thomas Rosenberg, and Paul A. Sieving for providing fundus photos, electroretinograms, and other clinical data on their patients, and Terri McGee and Kevin McDermott for expert construction of the figures.

References (75)

  • K.M. Boycott et al.

    Evidence for genetic heterogeneity in X-linked congenital stationary night blindness

    Am J Hum Genet

    (1998)
  • D.A. Hill et al.

    Cone electroretinograms in congenital nyctalopia with myopia

    Am J Ophthalmol

    (1974)
  • G. Panozzo et al.

    Association of xerophthalmia, flecked retina, and pseudotumor cerebri caused by hypovitaminosis A

    Am J Ophthalmol

    (1998)
  • E.L. Berson et al.

    Paraneoplastic night blindness with malignant melanoma

    Am J Ophthalmol

    (1988)
  • M.A. Musarella et al.

    Assignment of the gene for complete X-linked congenital stationary night blindness (CSNB1) to Xp11.3

    Genomics

    (1989)
  • C. Snyder

    Jean Nougaret, the butcher from Provence, and his family

    Arch Ophthalmol

    (1963)
  • J.C. Armington et al.

    Electroretinogram in nyctalopia

    Arch Ophthalmol

    (1954)
  • P. Gouras et al.

    Retinitis pigmentosa in abetalipoproteinemiaeffect of vitamin A

    Invest Ophthalmol Vis Sci

    (1971)
  • P. Christian et al.

    Night blindness of pregnancy in rural Nepal—nutritional and health risks

    Int J Epidemiol

    (1998)
  • G. Schubert et al.

    Beitrag zur Analyse des menschlichen Elektroretinogramms

    Ophthalmologica

    (1952)
  • Y. Miyake et al.

    Congenital stationary night blindness with negative electroretinogram. A new classification

    Arch Ophthalmol

    (1986)
  • E. Nettleship

    A history of congenital stationary night-blindness in nine consecutive generations

    Trans Ophthalmol Soc UK

    (1907)
  • H. Truc

    Généalogie d’une famille héméralope depuis prés de trois siècles, 270 ans, 10 générations, 2121 membres, 135 héméralopes

    Bull Soc Ophtalmol Fr

    (1909)
  • C. Dejean et al.

    Note sur la genealogie de la famille Nougaret, de Vendémian

    Bull Soc Ophtalmol Fr

    (1949)
  • R.P. Kline et al.

    Generation of b-wave currents in the skate retina

    Proc Natl Acad Sci USA

    (1978)
  • E.L. Berson

    Retinitis pigmentosa

    The Friedenwald Lecture. Invest Ophthalmol Vis Sci

    (1993)
  • N.S. Peachey et al.

    A form of congenital stationary night blindness with apparent defect of rod phototransduction

    Invest Ophthalmol Vis Sci

    (1990)
  • T.P. Dryja et al.

    Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness

    Nature Genet

    (1993)
  • P.A. Sieving et al.

    Dark-lightmodel for nightblindness from the human rhodopsin Gly-90–>Asp mutation

    Proc Natl Acad Sci USA

    (1995)
  • N. Al-Jandal et al.

    A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness

    Hum Mutat

    (1999)
  • D.M. Defoe et al.

    Rhodopsin chromophore exchanges among opsin molecules in the dark

    Invest Ophthalmol Vis Sci

    (1983)
  • V.R. Rao et al.

    Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness

    Nature

    (1994)
  • K. Fahmy et al.

    Spectroscopic evidence for altered chromophore–protein interactions in low-temperature photoproducts of the visual pigment responsible for congenital night blindness

    Biochem

    (1996)
  • F. Cunier

    Héméralopie héréditaire depuis deux siécles dans une famille de la commune de Vendémian, à cinq lieues de Montpellier

    Annal d’Ocul

    (1838)
  • F. Cunier

    Histoire d’une héméralopie héréditare depuis deux siècles dans une famille de la commune de Vendémian, près Montpellier

    Ann Soc méd Gand

    (1838)
  • M.A. Sandberg et al.

    Rod electroretinograms in an elevated cyclic guanosine monophosphate-type human retinal degeneration

    Invest Ophthalmol Vis Sci

    (1990)
  • M.A. Sandberg et al.

    Rod and cone function in the Nougaret form of stationary night blindness

    Arch Ophthalmol

    (1998)

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    ☆

    This work was supported by grants EY08683 and EY00169 from the National Institutes of Health, Bethesda, Maryland, grants from the Foundation Fighting Blindness, Baltimore, Maryland, and donations to the Taylor Smith Laboratory and the Ocular Molecular Genetics Institute of the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

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