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Phosphorylation is thought to be an essential first step in the prompt deactivation of photoexcited rhodopsin.In vitro, the phosphorylation can be catalyzed either by rhodopsin kinase (RK) or by protein kinase C (PKC). To investigate the specific role of RK, we inactivated both alleles of the RK gene in mice. This eliminated the light-dependent phosphorylation of rhodopsin and caused the single-photon response to become larger and longer lasting than normal. These results demonstrate that RK is required for normal rhodopsin deactivation. When the photon responses of RK−/− rods did finally turn off, they did so abruptly and stochastically, revealing a first-order backup mechanism for rhodopsin deactivation. The rod outer segments of RK−/− mice raised in 12-hr cyclic illumination were 50% shorter than those of normal (RK+/+) rods or rods from RK−/− mice raised in constant darkness. One day of constant light caused the rods in the RK−/− mouse retina to undergo apoptotic degeneration. Mice lacking RK provide a valuable model for the study of Oguchi disease, a human RK deficiency that causes congenital stationary night blindness.

Although rhodopsin's role in activating the phototransduction cascade is well known, the processes that deactivate rhodopsin, and thus the rest of the cascade, are less well understood. At least three proteins appear to play a role: rhodopsin kinase, arrestin and recoverin. Here we review recent physiological studies of the molecular mechanisms of rhodopsin deactivation. The approach was to monitor the light responses of individual mouse rods in which rhodopsin was altered or arrestin was deleted by transgenic techniques. Removal of rhodopsin's carboxy-terminal residues which contain phosphorylation sites implicated in deactivation, prolonged the flash response 20-fold and caused it to become highly variable. In rods that did not express arrestin the flash response recovered partially, but final recovery was slowed over 100-fold. These results are consistent with the notion that phosphorylation initiates rhodopsin deactivation and that arrestin binding completes the process. The stationary night blindness of Oguchi disease, associated with null mutations in the genes for arrestin or rhodopsin kinase, presumably results from impaired rhodopsin deactivation, like that revealed by the experiments on transgenic animals.

Objective To assess the clinical and molecular genetic studies of patients with autosomal recessive retinitis pigmentosa associated with a mutation in the arrestin gene. Design Results of molecular genetic screening and case reports with DNA analysis and clinical features. Setting University medical center. Patients One hundred twenty anamnestically unrelated patients with autosomal recessive retinitis pigmentosa. Methods DNA analysis was performed by single strand conformation polymorphism followed by nucleotide sequencing to search for a mutation in exon 11 of the arrestin gene. Clinical features were characterized by visual acuity slitlamp biomicroscopy, fundus examinations, fluorescein angiography, kinetic visual field testing, and electroretinography. Results We identified 3 unrelated patients with retinitis pigmentosa associated with a homozygous 1-base-pair deletion mutation in codon 309 of the arrestin gene designated as 1147delA. All 3 patients showed pigmentary retinal degeneration in the midperipheral area with or without macular involvement. Patient 1 had a sibling with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degeneration associated with a golden-yellow reflex in the peripheral fundus. Patients 1 and 3 showed features of retinitis pigmentosa without the golden-yellow fundus reflex. Conclusions Although the arrestin 1147delA has been known as a frequent cause of Oguchi disease, this mutation also may be related to the pathogenesis of autosomal recessive retinitis pigmentosa. This phenomenon may provide evidence of variable expressivity of the mutation in the arrestin gene.

Arrestins are soluble cytoplasmic proteins that bind to G-protein-coupled receptors, thus switching off activation of the G protein and terminating the signalling pathway that triggers the cellular response. Although visual arrestin has been shown to quench the catalytic activity of photoexcited, phosphorylated rhodopsin in a reconstituted system, its role in the intact rod cell remains unclear because phosphorylation alone reduces the catalytic activity of rhodopsin. Here we have recorded photocurrents of rods from transgenic mice in which one or both copies of the arrestin gene were disrupted. Photoresponses were unaffected when arrestin expression was halved, indicating that arrestin binding is not rate limiting for recovery of the rod photoresponse, as it is in Drosophila . With arrestin absent, the flash response displayed a rapid partial recovery followed by a prolonged final phase. This behaviour indicates that an arrestin-independent mechanism initiates the quench of rhodopsin's catalytic activity and that arrestin completes the quench. The intensity dependence of the photoresponse in rods lacking arrestin further suggests that, although arrestin is required for normal signal termination, it does not participate directly in light adaptation.

Oguchi disease is a recessively inherited form of stationary night blindness due to malfunction of the rod photoreceptor mechanism. Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon. Recently a defect in arrestin, a member of the rod phototransduction pathway, was found to cause this disease in some Japanese patients1. As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase. This report describes an analysis of the arrestin and rhodopsin kinase genes in three unrelated cases of Oguchi disease. No defects in arrestin were detected, but all three cases had mutations in the rhodopsin kinase gene. Two cases were found to be homozygous for a deletion encompassing exon 5, predicted to lead to a nonfunctional protein. The third case was a compound heterozygote with two allelic mutations, a missense mutation (Va1380Asp) affecting a residue in the catalytic domain, and a frameshift mutation (Ser536(4-bp del)) resulting in truncation of the carboxy terminus. Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness.

Oguchi disease is known as a type of autosomal recessive congenital stationary night blindness with a golden yellow-reflex of the fundus(1–3). Characteristic clinical features are Mizuo-Nakamura phenomenon(4) and extremely retarded dark adaptation of rod photoreceptors. The cone function usually appears normal.

Oguchi disease is a form of retinal dysfunction in which congenital night blindness is accompanied by a light-dependent discoloration of the fundus, extremely slow dark adaptation and an abnormal rod electroretinogram. This autosomal recessive condition is generally considered to be non-progressive however Oguchi disease and progressive retinal pigmentary degeneration or congenital stationary night blindness has occurred in the same families and even in the same patients. Oguchi disease may therefore represent a disorder involving features of both congenital stationary night blindness and retinitis pigmentosa. Here we summarise molecular genetic analyses which indicate that mutations in the arrestin gene are responsible for at least some cases of Oguchi disease in the Indian and Japanese populations. We speculate that the light-dependent fundus discoloration characteristic of Oguchi disease may reflect hyper-activity of the phototransduction pathway resulting from failure of arrestin to bind to and quench light-activated rhodopsin.

We identified a novel AvaI polymorphism within 3' non-coding region within exon 5 of the human rhodopsin gene and determined the allele frequency in a Japanese population. The polymorphism was found to be due to A/G transversion at nucleotide 5510 of the gene.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness with all other visual functions, including visual acuity, visual field, and colour vision being usually normal. A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light ('Mizuo phenomenon'; Fig. 1). The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally. The locus for Oguchi disease was recently mapped between D2S172 and D2S345 on distal chromosome 2q by linkage analysis. Interestingly, the gene for arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction, also maps to this region of chromosome 2q (refs 6, 7). Here we report that in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene, predicting a shift in the reading frame and a premature termination of translation which may result in 'functional null alleles.'

• Four unrelated males with X-linked retinoschisis and a golden fundus reflex had Mizuo-Nakamura phenomenon, which, to our knowledge, has been described only in Oguchi's disease and X-linked cone dystrophy. These findings, together with experimental observations and data from the literature, led us to hypothesize that the Mizuo-Nakamura phenomenon is caused by an excess of extracellular potassium in the retina as a result of a decreased potassium scavenging capacity of retinal Muller cells.

Purpose The only mutations reported to date in Japanese patients with Oguchi disease, a rare form of stationary night blindness with autosomal recessive transmission, have been in the SAG (arrestin) gene. The objective of this study was to describe the ophthalmic features and a novel mutation in the GRK1 (rhodopsin kinase) gene in 2 Japanese patients with Oguchi disease. Design Molecular genetic and observational case study. Participants A consanguineous family including 2 siblings with Oguchi disease (a 35-year-old man and a 31-year-old woman). Methods Best-corrected visual acuity (BCVA), fundus examinations, Goldmann perimetry, color vision tests, and full-field electroretinograms (ERGs) were evaluated. Mutation screening of the SAG and GRK1 genes was performed with polymerase chain reaction amplification and direct sequencing. Main Outcome Measures Mutations in the GRK1 gene, BCVA, color vision, fundus photographs, visual fields, and ERG findings. Results Molecular analysis revealed a novel homozygous missense mutation (p.P391H) in the GRK1 gene in both patients. Proline 391 is not only within the functionally important catalytic domain, but is also a phylogenetically conserved amino acid residue among GRK1 orthologs and homologs. No mutation was found in the SAG gene. The unaffected parents were heterozygous carriers of the mutation. Both patients had night blindness, 1.5 BCVA for each eye, normal color vision, and typical fundus appearance with golden-yellow discoloration. The visual fields were normal in the male sibling. The ERGs showed no rod B waves, reduced standard combined responses, and markedly reduced single-flash cone and 30-Hz flicker responses in both patients. Conclusions A novel homozygous GRK1 mutation (p.P391H) was found in 2 Japanese siblings with Oguchi disease. Visual function in the 2 patients has not deteriorated with age, indicating that the disease is stationary. This is the first report of any patient with GRK1-associated Oguchi disease with markedly reduced cone responses.

Objective To characterize clinical features of patients with Oguchi disease associated with a homozygous deletion of adenine at nucleotide 1147 (1147delA) in codon 309 in the arrestin gene. Methods Mutation screening by single-strand conformation polymorphism analysis was done, followed by sequencing. Ophthalmologic testing included evaluation of visual acuity and color vision, fundus examination, electroretinography, fluorescein angiography, evaluation of kinetic visual field, and dark adaptometry. Nine patients with Oguchi disease from seven unrelated families and family members who were unaffected by the disease were examined. Results A homozygous 1147delA mutation in the arrestin gene was identified in eight patients from six families with Oguchi disease. All patients who were examined exhibited a golden-yellow retinal reflex associated with Mizuo-Nakamura phenomenon and impairment of rod function in dark adaptation tests, although fundus examination showed slight variation in these findings. Four patients with the mutation had slightly reduced visual acuity, and the electroretinograms of three patients showed slightly reduced amplitudes during 30-Hz flicker electroretinography. Conclusion Patients with Oguchi disease associated with the arrestin 1147delA mutation typically demonstrate retarded rod adaptation, whereas some patients have slightly impaired cone function.

• We encountered a new X-linked recessive cone dystrophy in which patients have a greenish-golden tapetallike sheen of the retina; while the retinal sheen and electroretinographic abnormalities are present from childhood, patients are not symptomatic until adult years. All of the male patients tested showed evidence of cone dysfunction on color vision testing, dark adaptometry, and electroretinography. After three hours of dark adaptation, the tapetal-like sheen disappeared, with most areas changing from greenish-golden shades to orange-red hues (Mizuo-Nakamura phenomenon). One male patient had a retinal detachment from atrophic round holes in the equatorial retina.