Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture  Thaddeus P Dryja, MD  American Journal of Ophthalmology  Volume 130, Issue 5, Pages 547-563 (November 2000) DOI: 10.1016/S0002-9394(00)00737-6

Figure 1 Schematic dark-adaptation curves in normal individuals and in patients with stationary night blindness. In all three graphs, the y axis is the minimal intensity of a perceptible spot of light (logarithmic scale, units are microapostilbs) at the time (minutes) designated on the x axis after exposure to light that bleaches 25% or more of the rhodopsin in each rod photoreceptor. The solid curve in each panel represents the normal dark-adaptation curve. The top left graph has the normal curve labeled with its components: the initial cone branch which ends at the rod-cone break and is followed by the rod branch. (Top left) The dark-adaptation curves found in patients with the Nougaret or Rambusch forms of dominant stationary night blindness (which are very similar and are represented by a single dashed line)27,29 and in a patient with the dominant rhodopsin mutation Ala292Glu causing stationary night blindness (dotted line, based on unpublished observations of Drs. Berson and Sandberg). (Top right) Dark-adaptation curves from patients with complete (dashed line) or incomplete (dotted line) X-linked stationary night blindness (XL-SNB).10 (Bottom) Dark-adaptation curves characteristic of fundus albipunctatus53 (dashed line) and Oguchi disease36,38 (dotted line). The rod-cone break in both fundus albipunctatus and Oguchi disease has been arbitrarily placed at the 2-hour time point; in reality, it could be somewhat before or after this time point depending on the degree of light exposure preceding the evaluation of dark adaptation. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 2 Electroretinograms of a normal individual and patients with forms of stationary night blindness. The tracings in the top row are the responses to single flashes (repeated every 2 seconds, or 0.5 Hz) of blue light that is so dim that only rods are stimulated. The middle row shows the responses to 0.5-Hz, bright, white flashes that stimulate both rods and cones. The bottom row shows the responses to bright, white light flashing 30 times per second (30 Hz); cones but not rods elicit individual responses to light flashing at this frequency. Thus, going from the top to bottom rows, one observes normal rod-isolated responses, combined rod-plus-cone responses, and cone-isolated responses. The time of the light flashes is denoted by the vertical dashed line in the top and middle rows and by the solid vertical lines within the tracings of the bottom row. The letters “a” and “b” in the normal rod-plus-cone electroretinogram (left column, middle row) label the a-wave and b-wave, respectively. The arrows in the tracings of the bottom row denote the cone peak implicit times (that is, the time interval between a light flash and the corresponding peak amplitude). In all tracings, two or three consecutive sweeps are superimposed. The calibration symbol in the lower right corner designates 50 ms horizontally and 100 μV vertically. The column headings refer to the genetic defect causing each patient’s night blindness. Note that the patients with rhodopsin, transducin, and rhodopsin kinase mutations have no observable rod b-waves with these test conditions, whereas the patient with a defective 11-cis RDH (fundus albipunctatus) has a subnormal rod b-wave that becomes normal in amplitude after 5 hours of dark adaptation. Mixed rod-plus-cone responses to 0.5-Hz flashes of bright white light (middle row) are without a prominent cornea-positive b-wave (rhodopsin and rhodopsin kinase cases) or have subnormal b-waves (transducin) except for fundus albipunctatus where the rod-plus-cone b-wave is normal. The rod-plus-cone electroretinograms in fundus albipunctatus would be subnormal after 45 minutes of dark adaptation if the dark-adaptation period had been preceded by exposure to intensely bright light that would bleach a large proportion of the patient’s rhodopsin. In all of these forms of stationary night blindness, cone electroretinograms in response to 30-Hz white flickering light are normal or near-normal in amplitude and have normal peak implicit times (that is, 32 ms or less). American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 3 Diagram of the rod phototransduction cascade indicating those proteins defective in forms of stationary night blindness. In the normal pathway, rhodopsin (rho) becomes photoactivated (middle left of figure) and stimulates a number of transducin (Ta) molecules from the inactive, GDP-bound state (Ta-GDP) to the active GTP-bound state (Ta-GTP, four of which are indicated in the figure). Each activated transducin molecule activates in turn a cGMP-phosphodiesterase complex (PDE) formed by an a, b, and two g subunits (only one complex is shown at the top of the figure). Phosphodiesterase hydrolyzes cGMP in the cytoplasm, which will serve to close cGMP-gated cation channels on the cell membrane (not shown), resulting in hyperpolarization of the cell. In the meantime, the photoactivated rhodopsin is ultimately phosphorylated by rhodopsin kinase and then forms a complex with arrestin (top right of figure). The chromophore all-trans retinal separates from rhodopsin, is converted to all-trans retinol, and travels to the retinal pigment epithelium (RPE, denoted by shaded box) to be isomerized back to 11-cis retinol (bottom of figure); 11-cis retinol is converted 11-cis retinal by the enzyme 11-cis retinol dehydrogenase, and the 11-cis retinal travels back to the photoreceptors to combine with opsin that had been dephosphorylated by the action of phosphatase. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 4 Schematic diagram of rhodopsin showing the location of amino acid residues that are altered in cases of stationary night blindness. The protein has an amino terminus in the intradiscal space, seven transmembrane domains, and a carboxy terminus in the cytoplasm. The lysine residue highlighted with a square in the seventh transmembrane domain forms a covalent bond with the chromophore (11-cis retinal, not shown in the figure). The asterisks denote serine and threonine residues near the carboxy terminus that are phosphorylated by rhodopsin kinase. The locations of two asparagine residues (symbol N) near the amino terminus that are glycosylated are shown. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 5 Photographs of fundi of patients with stationary night blindness. (Left) A 34-year-old patient with night blindness and the rhodopsin mutation Ala292Glu.18 There is no vascular attenuation or other stigmas of retinal degeneration. A choroidal nevus is incidentally present (courtesy EL Berson). (Right) Composite fundus photograph of a 63-year-old affected member of the family with the rhodopsin mutation Gly90Asp (courtesy PA Sieving).19 This patient had night blindness throughout life. Corrected visual acuities are 20/20 in both eyes. There is slight vascular attenuation. Modest atrophy of the retina with some retinal pigmentary deposits are visible in the inferonasal retina. This patient had Goldmann visual fields extending to 115 degrees with the I4e target, with some constriction superiorly corresponding to the fundus pathology, and full-field cone electroretinogram amplitudes at the lower limit of normal (fields and electroretinograms not shown). American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 6 (Left) Fundus photograph of a 48-year-old man with Nougaret night blindness resulting from the mutation Gly38Asp in the gene encoding rod α-transducin (courtesy E Berson).27 (Right) Fundus photograph of a 14-year-old male with Rambusch night blindness resulting from the mutation His258Asn in the gene encoding the β subunit of rod cGMP-phosphodiesterase (courtesy T Rosenberg).29–31 The fundi in both the Nougaret and Rambusch forms of stationary night blindness have no vascular attenuation or other signs of retinal degeneration. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 7 Fundus photographs of patients with Oguchi disease. (Top left) A patient homozygous for the arrestin mutation Asn309(1-bp del) (also known as 1147delA) after 12 hours of dark adaptation. (Top right) After 30 minutes of light adaptation, the same region of the retina has a golden color (the Mizuo-Nakamura phenomenon). (Bottom left) Fundus photograph of a 55-year-old woman with Oguchi disease (from Nakazawa and associates, Retina69 reprinted with permission). (Bottom right) Fundus photograph of her 58-year-old brother with retinitis pigmentosa. Both siblings were homozygous for the arrestin mutation Asn309(1-bp del), a reported cause of Oguchi disease.50,69 (Photographs courtesy M Nakazawa.) American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 8 (Left) Fundus photograph of fundus albipunctatus in a 49-year-old woman who is homozygous for the missense mutation Gly238Trp in the gene encoding 11-cis RDH (from Yamamoto and associates, Nature Genetics53 reprinted with permission). Numerous subretinal dots are present, including some in the macula. (Right) Fundus photograph of a 49-year-old man with fundus albipunctatus resulting from a mutation in 11-cis RDH and a “bull’s-eye” maculopathy and numerous dots elsewhere in the retina (courtesy Y Miyake). The electroretinograms of this patient are shown in Figure 9. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 9 Full-field electroretinograms of the 49-year-old man with fundus albipunctatus and cone degeneration. These electroretinograms were recorded with techniques somewhat different from those described in the legend of Figure 2.10 The photoreceptor mechanism evaluated is labeled at the left of each row and corresponds to that in Figure 2. The rod (scotopic) signal (top row) achieves a normal amplitude within 3 hours of dark adaptation, whereas the cone electroretinograms to 30-Hz flickering light (bottom row) have an abnormally reduced amplitude. Calibration symbols for each row are at the lower right corner of the normal electroretinogram waveforms in the left column (courtesy Y Miyake). American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 10 Fundus photographs of (left) a 19-year-old man with X-linked incomplete stationary night blindness and visual acuity of 20/30, and (right) an 18-year-old man with X-linked complete stationary night blindness and visual acuity of 20/50 (courtesy Y Miyake). Despite the subnormal visual acuities, the maculas appear normal. The electroretinograms of these patients are shown in Figure 11. American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)

Figure 11 Electroretinograms of (left) a normal individual, (middle) a 19-year-old man with X-linked incomplete stationary night blindness, and (right) an 18-year-old man with X-linked complete stationary night blindness (SNB). The rod-plus-cone electroretinograms in the middle row shown here were elicited in response to light flashes considerably more intense than used for the electroretinograms in Figure 2. These intense light flashes normally produce a larger a-wave which is mostly due to the rod photoreceptors. The patient with incomplete night blindness has an intact rod a-wave (seen in the middle row) and a reduced rod b-wave (seen in the top row) that is slightly delayed in timing. This patient also has a markedly reduced cone amplitude in response to 30-Hz light pulses (bottom row). The patient with complete night blindness has an intact rod a-wave (middle row), no rod b-wave (top row), and normal cone amplitude (bottom row) (courtesy Y Miyake). American Journal of Ophthalmology 2000 130, 547-563DOI: (10.1016/S0002-9394(00)00737-6)