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The available literature regarding Oguchi disease is limited, with around 50 cases described to date. Caused by mutations to either the SAG gene coding for arrestin (Hayashi et al. in Ophthalmic Res 46:175–180, 2011) or the GRK1 gene coding for rhodopsin kinase (Yamamoto et al. in Nat Genet 15:175–178. https://doi.org/10.1038/ng0297-175 , 1997), Oguchi disease is an autosomal recessive condition with a good visual prognosis. The clinical diagnosis of the condition is based on the presence of night blindness (nyctalopia), as well as fundoscopic observation of the Mizuo–Nakamura phenomenon. The Mizuo–Nakamura phenomenon refers to a fundus discolouration described as a golden-brown colour with a yellow-grey metallic sheen most prominent in the peripheral retina; after prolonged dark adaptation, the fundus appears normal. The prevalence of Oguchi disease is highest in Japan, particularly with SAG mutations (Nakazawa et al. in Retina 17:17–22, 1997), although patients from Europe, Pakistan and India have also been described. Formal diagnosis requires genetic testing. Wide-field fundus images were obtained in both dark-adapted and light-adapted retina. Optical coherence tomography and dark-adapted electroretinography responses were used to further characterize the clinical phenotype. Existing descriptions of Oguchi disease have been limited by available technology. The flashes required for 45°-montage photographs in a dark-adapted eye quickly cause light adaptation. Recent advances in technology enable the capture of larger retinal areas in a single image. Wide-field 133° images were obtained of the native and dark-adapted fundus in natural colour. To our knowledge, these represent the first reported single-wide-field images of Oguchi disease, showing the characteristic Mizuo–Nakamura phenomenon in true colour. Genetic testing revealed a novel homozygous mutation in GRK1. Here, we demonstrate how characterizing this condition with single-shot true-colour wide-field imaging has distinct advantages over scanning laser technology, which applies artificial colouration, or stitched true-colour images. Images captured with wide-field systems create a much better representation of the native and dark-adapted fundus than can be observed by the ophthalmologist using direct fundoscopy and are essential in the clinical characterization of new mutations.

Background: The GNAT1 gene encodes the alpha-subunit of transducin in rod photoreceptors and is an important part of the phototransduction cascade. Defects in GNAT1 are very rare but have been identified in autosomal dominant and recessive congenital stationary night blindness (CSNB) and autosomal recessive rod-cone dystrophy. The purpose of this study was to determine the phenotype-genotype relationship in a non-consanguineous Japanese family with a GNAT1 mutation.Methods: Detailed ophthalmic examinations were performed on the patients and their family members. Whole exome sequencing (WES) was applied to the DNA obtained from the family members. Sanger sequencing and co-segregation analyses were performed to identify the most likely pathogenic variant.Results: Two female (13- and 11-years) and one male (15-years) patients from a family had night blindness from their childhood. The fundus had a mild golden appearance regardless of the state of light- or dark-adaptation. Electroretinographic (ERG) analyses showed that the scotopic a-wave was extinguished, and the mixed rod-cone responses were severely reduced with an electronegative form in patients. The shapes of the dark-adapted ERGs were similar to those recorded from patients with Oguchi disease. We identified a homozygous in-frame deletion c.818_820delAGA, p.Lys273del in the GNAT1 gene. Variants were verified by Sanger sequencing and co-segregated with the disease in five members of the family.Conclusions: Our findings indicate that a recessive GNAT1 mutation found in this family could be the cause of the golden appearance of the fundus and negative ERGs with reduced a-waves, and nearly absent b-waves in the mixed rod-cone ERGs.

Biallelic mutations in G‐Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in‐depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure‐based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease‐causing variants may impede protein function in‐silico., In this study, Poulter et al. expand the number of mutations in Rhodopsin Kinase (GRK1), associated with Oguchi disease, from 13 to 21. The authors compare disease associated mutations with likely nonpathogenic variants in a range of bioinformatic prediction software. In silico analyses of the mutations, using a homology model, suggest mutations result in one of three potential mechanisms of disease: loss of protein, loss of kinase function or a failure of prenylation leading to mislocalisation of the protein.

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRD, with the first approved gene therapy and the commencement of multiple therapy trials. The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD. Herein we present in a comprehensive and concise manner the imaging findings of: (I) macular dystrophies (MD) [Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), pattern dystrophy (PRPH2), Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)], (II) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4 and RPGR), (III) cone dysfunction syndromes [achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6], blue-cone monochromatism (OPN1LW/OPN1MW array), oligocone trichromacy, bradyopsia (RGS9/R9AP) and Bornholm eye disease (OPN1LW/OPN1MW), (IV) Leber congenital amaurosis (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (V) rod-cone dystrophies [retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)], (VI) rod dysfunction syndromes (congenital stationary night blindness, fundus albipunctatus (RDH5), Oguchi disease (SAG, GRK1), and (VII) chorioretinal dystrophies [choroideremia (CHM), gyrate atrophy (OAT)].

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness (CSNB) characterized by specific features such as golden-brown discoloration of the fundus called Mizuo-Nakamura phenomenon which is distinguishable by fundoscopy, and retinography. Clinical diagnosis is confirmed through genetic test. Two known genes in pathogenesis of Oguchi disease are SAG and GRK1. A 35-year-old Iranian male exhibiting the clinical features of congenital stationary night blindness, was referred to the genetic clinic of Dr. Farhud, Tehran, Iran in 2012 and examined. Ophthalmic examination including slit-lamp biomicroscopy, perimetry and funduscopy was performed. Additionally, the full-field electroretinography and molecular testing for congenital stationary night blindness were performed. Molecular genetic tests, including the analysis of GSK1 and SAG genes exon-intron boundaries were performed for this patient and his family. According to the sequencing results, we did not find any mutation in GSK1 gene. However, a new homozygote mutation at location chr2:233320735, c.517delC, p.P96LfsX28 was identified in exon four of SAG gene. This deletion causes a frame shift mutation, and premature stop codon that results in deletion of about 281 amino acid residues of S-antigen visual arrestin protein (from entire C-terminal). This mutation was also found in patient’s parents and one of his sister as heterozygote form. This is the first molecular evidence for SAG gene mutation in an Iranian family affected with Oguchi disease type 1. The identification of the new c.517delC, p.P96LfsX28 mutation in this family with Oguchi disease can confirm the pathogenicity of this variant.

PurposeBiallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all GRK1 pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified new GRK1 pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).

Oguchi disease is a rare form of congenital stationary night blindness with an autosomal recessive inheritance pattern. The presence of S‑antigen (SAG) and G‑protein‑dependent receptor kinase 1 (GRK1) mutations were investigated in the family members with Oguchi disease. All exons of the SAG and GRK1 genes were amplified by polymerase chain reaction and sequenced. The patients were shown to have characteristic clinical features of Oguchi disease. Gene analysis determined a novel GRK1 mutation c.923T>C, which caused Oguchi disease in all siblings. This mutation, was demonstrated by amino acid alignment analysis to be in a phylogenetically conserved region and resulted in an amino acid change from leucine to proline at position 308. Thus, the present study reports a novel missense mutation of GRK1 in the affected members of a consanguineous Turkish family. Homozygosity at position 308, which resides in the catalytic domain of the GRK1 gene, is the cause of Oguchi disease in this Turkish family.

Congenital stationary night blindness (CSNB) refers to a group of genetically and clinically heterogeneous retinal disorders. Seventeen different genes with more than 360 different mutations and more than 670 affected alleles have been associated with CSNB, including genes coding for proteins of the phototransduction cascade, those important for signal transmission from the photoreceptors to the bipolar cells or genes involved in retinoid recycling in the retinal pigment epithelium. This article describes the phenotypic characteristics of different forms of CSNB that are necessary for accurate diagnosis and to direct and improve genetic testing. An overview of classical and recent methods used to identify specific CSNB genotypes is provided and a meta-analysis of all previously published and novel data is performed to determine the prevalence of disease-causing mutations. Studies of the underlying molecular pathogenic mechanisms based on cell culture techniques and animal studies are outlined. The article highlights how the study of CSNB has increased understanding of the mechanisms of visual signalling in the retina, likely to prove important in developing future treatments for CSNB and other retinal disorders.

Oguchi disease, is a very rare form of night blindness caused by biallelic variations in the SAG or GRK1 genes, both involved in rod restoration after light stimuli. Here we report the clinical and genetic findings of an 8-year old boy with a history of reduced visual acuity, nyctalpia and hemeralopia. Clinical findings, in particular the Mizuo-Nakamura phenomenon, were compatible with a diagnosis of Oguchi disease. Genetic testing revealed a novel missense homozygous variation in the SAG gene. This is the first evidence that the disease can be caused by missense variations in this gene.

Arrestin-14 binds light-activated rhodopsin phosphorylated by GRK1 (a.k.a. rhodopsin kinase) with high affinity (1), ensuring the termination of light-induced signaling with sub-second kinetics (2). Arrestin-1 knockout in mice dramatically slows the photoresponse shutoff in rod (3) and cone (4) photoreceptors. Arrestin-1 deficiency in humans results in Oguchi disease, a form of stationary night blindness (5). Arrestin-1 is expressed at very high levels in both photoreceptor types, being the second most abundant signaling protein after corresponding opsins (4, 6, 7). Considering that the rhodopsin concentration in rod outer segments (OS) is ~3 mM (8), the average cytoplasmic concentration of arrestin-1 (which is expressed at ~0.8:1 ratio to rhodopsin (6, 7, 9)) is expected to be >1 mM (1). Dark-adapted rods are used in most studies of the molecular mechanisms of rod signaling in genetically modified mice (reviewed in (10–12)). In the dark, ~85% of arrestin-1 resides in the inner segments, cell bodies, and synaptic terminals (6, 9, 13–15), which brings its concentration in these compartments to >2 mM (9). While the majority of the functional studies were performed in mice and humans, the biochemical properties of arrestin-1 were mostly studied using bovine protein. Bovine arrestin-1 robustly self-associates (16, 17), cooperatively forming dimers and tetramers (16, 18, 19). It is unclear whether this is a peculiar property of bovine protein, or a common feature of mammalian arrestin-1 species. In addition, since only monomeric arrestin-1 binds rhodopsin and quenches the signaling (18), the concentration of the monomer is an important functional parameter; it can be calculated based on total arrestin-1 if the self-association constant(s) are known. In view of therapeutic potential of “enhanced” mutants that can compensate for deficits of rhodopsin phosphorylation in vivo (20), characterization of human arrestin-1 is particularly important. Therefore, we explored oligomerization of purified mouse and human arrestin-1 and found that self-association is a common feature of mammalian arrestin-1. Interestingly, we found that while the values of dimerization and tetramerization constants of arrestin-1 from three species are very different, the underlying molecular interactions appear to be similar: the same point mutations render bovine and mouse arrestin-1 constitutively monomeric.

The average person's eyes adapt to darkness within minutes. For those with Oguchi's disease, adaptation can be slowed to several hours. Oguchi disease is an autosomal recessive disorder that results in greatly slowed phototransduction. Phototransduction is a cascade reaction beginning with a photon activating rhodopsin in the rod and leading to hyperpolarization of the cell. Oguchi disease is caused by mutations in rhodopsin kinase which prevent the phosphorylation of rhodopsin, lowering rhodopsin's affinity for arrestin. This reduced ability to bind arrestin decreases the speed in which rhodopsin is deactivated and prepped to reactivate. After a long period in a dark environment, the rhodopsin is eventually deactivated by arrestin, allowing it to be recycled. The Hartford Union High School SMART (Students Modelling a Research Topic) Team has designed a model of rhodopsin kinase to investigate its structure-function relationship. Oguchi disease can be caused by two different mutations in rhodopsin kinase:...

We report that visual arrestin can regulate retinal release and late photoproduct formation in rhodopsin. Our experiments, which employ a fluorescently labeled arrestin and rhodopsin solubilized in detergent/phospholipid micelles, indicate that arrestin can trap a population of retinal in the binding pocket with an absorbance characteristic of Meta II with the retinal Schiff-base intact. Furthermore, arrestin can convert Metarhodopsin III (formed either by thermal decay or blue-light irradiation) to a Meta II-like absorbing species. Together, our results suggest arrestin may be able to play a more complex role in the rod cell besides simply quenching transducin activity. This possibility may help explain why arrestin deficiency leads to problems like stationary night blindness (Oguchi disease) and retinal degeneration.

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.

We analyzed the change in the ERG rod a-wave waveform during the course of dark adaptation in two patients with Oguchi disease. Two Japanese patients showed a homozygous arrestin 1147delA mutation. Scotopic flash ERGs were recorded after different periods of dark adaptation. ERG rod a-waves were obtained after subtraction of the cone ERG contribution. The rod a-waves were fitted with a model of the rod receptor signal. The parameters, Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. Longer periods in the dark produced larger rod a-wave but only to the first flash presented. The amplitude of the response to subsequent flashes was essentially independent of the period of dark adaptation. Rm(p3) increased with advance of dark adaptation. However, S was nearly constant. Our results suggest that the cause of delayed dark adaptation is not to be sought in the activation of phototransduction process or the regeneration of rhodopsin per se but rather in the deactivation process of the phototransduction cascade.

Purpose To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG. Methods Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members. Results Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability. Conclusions This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.

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.

Purpose: To investigate the ectopic transcription of arrestin in various human organs and tissues. Methods: Reverse transcriptase–polymerase chain reaction was used to investigate the ectopic transcription of the arrestin gene in the retina, anterior capsule of the lens, iris, bulbar conjunctiva, muscle, skin, placenta, intestine, and human blood. In addition, we examined the expression of arrestin mRNA isolated from whole blood cells of patients with Oguchi disease who had the 1147delA mutation in the arrestin gene. Results: Arrestin was expressed at the mRNA level in all our samples. The mRNA isolated from the blood cells of Oguchi patients was not associated with the same 1147delA mutation as was reported earlier in the arrestin gene but had the normal sequence. Conclusions: These results demonstrate the ectopic transcription of the arrestin gene in various tissues and also suggest the possibility of RNA editing in the blood cells of Oguchi patients.

We examined the sequence of the arrestin gene in two unrelated patients with Oguchi disease. A 35-year-old woman and a 72-year-old man underwent a complete ophthalmological examination, including evaluation of visual acuity and color vision, fundus examination, and electroretinography. A golden-yellow discoloration was observed in their fundi. After 30 minutes of dark adaptation, the discoloration in the fundus disappeared. A deletion of an adenine in codon 309 of exon 11 of the arrestin gene was identified in both patients. Mutations in the arrestin are common in Japanese patients with Oguchi disease.

Rhodopsin kinase (RK), a rod photoreceptor cytosolic enzyme, plays a key role in the normal deactivation and recovery of the photoreceptor after exposure to light. To date, three different mutations in the RK locus have been associated with Oguchi disease, an autosomal recessive form of stationary night blindness in man characterized in part by delayed photoreceptor recovery [Yamamoto, S., Sippel, K. C., Berson, E. L. & Dryja, T. P. (1997) Nat. Genet. 15, 175–178]. Two of the mutations involve exon 5, and the remaining mutation occurs in exon 7. Known exon 5 mutations include the deletion of the entire exon sequence [HRK (X5 del) ] and a missense change leading to a Val380Asp substitution in the encoded product (HRK V380D ). The mutation in exon 7 is a 4-bp deletion in codon 536 leading to premature termination of the encoded polypeptide [HRK S536(4-bp del) ]. To provide biochemical evidence for pathogenicity of these mutations, wild-type human rhodopsin kinase (HRK) and mutant forms HRK V380D and HRK S536(4-bp del) were expressed in COS7 cells and their activities were compared. Wild-type HRK catalyzed light-dependent phosphorylation of rhodopsin efficiently. In contrast, both mutant proteins were markedly deficient in catalytic activity with HRK V380D showing virtually no detectible activity and HRK S536(4-bp del) only minimal light-dependent activity. These results provide biochemical evidence to support the pathogenicity of the RK mutations in man.

Rhodopsin kinase (RK), a specialized G-protein-coupled receptor kinase expressed in retina, is involved in quenching of light-induced signal transduction in photoreceptors. The role of RK in recovery after photoactivation has been explored in vitro and in vivo experimentally but has not been specifically defined in humans. We investigated the effects on human vision of a mutation in the RK gene causing Oguchi disease, a recessively inherited retinopathy. In vitro experiments demonstrated that the mutation, a deletion of exon 5, abolishes the enzymatic activity of RK and is likely a null. Both a homozygote and heterozygote with this RK mutation had recovery phase abnormalities of rod-isolated photoresponses by electroretinography (ERG); photoactivation was normal. Kinetics of rod bleaching adaptation by psychophysics were dramatically slowed in the homozygote but normal final thresholds were attained. Light adaptation was normal at low backgrounds but became abnormal at higher backgrounds. A slight slowing of cone deactivation kinetics in the homozygote was detected by ERG. Cone bleaching adaptation and background adaptation were normal. In this human in vivo condition without a functional RK and probable lack of phosphorylation and arrestin binding to activated rhodopsin, reduction of photolyzed chromophore and regeneration processes with 11- cis -retinal probably constitute the sole pathway for recovery of rod sensitivity. The role of RK in rods would thus be to accelerate inactivation of activated rhodopsin molecules that in concert with regeneration leads to the normal rate of recovery of sensitivity. Cones may rely mainly on regeneration for the inactivation of photolyzed visual pigment, but RK also contributes to cone recovery.

To analyze mutations of the arrestin/S-antigen (SAG) gene in nine newly identified Oguchi disease patients, and to examine whether the 926delA (formerly called 1147delA) mutation in the SAG gene is inherited from a single founder.DNA samples were assayed for mutations around nucleotide 926 of the SAG gene by direct sequencing, and analyzed for polymorphisms at codon 403 and IVS6-18 of the SAG gene by restriction analysis of polymerase chain reaction products.All nine newly identified patients were homozygous for the 926delA mutation and had the same haplotype at codon 403 and IVS6-18. These findings are identical to those of previous reports of four Japanese Oguchi disease patients.Mutation 926delA of the SAG gene is the main cause of Oguchi disease in Japanese. This mutation appears to have been inherited from a single founder.

Purpose To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Design Prospective, observational case series. Methods We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6 , 2 brothers with Oguchi disease caused by mutations in GRK1 , and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Results Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. Conclusions The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus.

Recent work has established potential new functional roles for NSF in the photoreceptor. First, the interaction of Arr1 and NSF is ATP-dependent, and the N-terminal domain of Arr1 interacts with the N and D1 junctional domains of NSF. The Arr1-NSF interactions are greater in the photoreceptor synaptic terminal in the dark. Furthermore, Arr1 enhances the NSF ATPase activity and increases the NSF disassembly activities, which are critical for NSF functions in sustaining a higher rate of exocytosis in the photoreceptor synapses and the compensatory endocytosis to retrieve vesicle membrane and vesicle proteins for vesicle recycling. These data demonstrate the Arr1 and NSF interaction are necessary for both maintenance and modulation of normal photoreceptor synaptic regulation. Second, NSF colocalizes and specifically binds to RP2, especially in the ciliary and synaptic region of the photoreceptor, and NSF-RP2 interaction may play an important role in membrane protein trafficking in the photoreceptor. Inherited retinal degeneration affects about 1 in 2,000-3,000 individuals in the world and is the leading cause of visual loss in young people and accounts for a large proportion of blindness in adult life. These studies accelerate our ability to gain insight into the diverse roles of the NSF in the photoreceptor cells and enable us to understand more precisely the molecular mechanisms underlying night blindness associated with clinically diagnosed Oguchi disease or other forms of retinitis pigmentosa.

KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

Arrestin is a 45 KDa protein and is mainly located in the membrane of photoreceptor rod cells and pineal gland. It is well known that 1147delA nutation in the arrestin gene causes Oguchi disease and autosomal recessive retinitis pigmentosa in Japanese patients. We examined expression of arrestin in mRNA isolated from whole blood cells of patients with Oguchi disease, who had the 1147delA mutation in the arrestin gene. Arrestin was expressed at the level of mRNA in all of three patients with Oguchi disease. mRNA from Oguchi patients did not have the same 1147delA mutation as was seen in the arrestin gene but had the normal sequence. The result indicated the possibility of RNA editing in blood cells in our patients.

Retinitis pigmentosa (RP) is a genetically heterogeneous group of diseases that show progressive degeneration of photoreceptors. Its incidence is about one in 3000 to 10,000 people in many countries, and it is a leading cause of blindness in the adult population. Several kinds of mutations have been reported in patients with autosomal recessive RP (arRP) in genes that are normally expressed in rod photoreceptors and that function in the process of phototransduction. Arrestin, one of the photoreceptorspecific proteins, plays a role in the cycle of rhodopsin regeneration. 1 A homozygous 1-base pair deletion mutation in the arrestin gene, designated the arrestin 1147delA, has been known as a frequent cause of Oguchi disease, a form of congenital stationary night blindness, in Japanese patients. 2 Interestingly, molecular genetic screening in patients with arRP, including a sibling of a patient with Oguchi disease, to search for mutations in the arrestin gene revealed that the same 1147delA mutation is also associated with arRP and is cosegregated with the disease. We report on 3 patients with arRP associated with the homozygous 1147delA mutation in the arrestin gene as evidence of variable expressivity of the mutation in the arrestin gene.

Purpose To report a Japanese patient with Oguchi disease and sectoral retinitis pigmentosa harboring a homozygous adenine deletion at position 1147 (1147delA) in the arrestin gene. Method Case report. Results In both eyes, golden discoloration with Mizuo-Nakamura phenomenon and tapetoretinal degeneration of the fundus were exhibited. Electroretinography showed abnormal a-wave and absent b-wave. The presence of 1147delA in the arrestin gene was demonstrated. Conclusions Our case provides further evidence of the close association of 1147delA in the arrestin gene in Japanese patients with Oguchi disease. Coexpression of both phenotypes of Oguchi disease and retinitis pigmentosa may suggest the possible involvement of additional defects of genes encoding the phototransduction proteins.

Oguchi disease is an autosomal recessive condition in which congenital night blindness is associated with a light-dependent golden fundus discoloration (Mizuo-Nakamura phenomenon). Co-segregation of Oguchi disease with chromosome 2q markers in an Indian pedigree (Maw et al., 1995) and a homozygous frameshift mutation in 5 of 6 apparently unrelated Japanese patients (Fuchs et al., 1995) has implicated the arrestin gene in this condition. Here, we report an Indian family in which two siblings affected by Oguchi disease are homozygous for a codon 193 Arg-to-ter mutation in the arrestin gene.

Following exposure of our eye to very intense illumination, we experience a greatly elevated visual threshold, that takes tens of minutes to return completely to normal. The slowness of this phenomenon of "dark adaptation" has been studied for many decades, yet is still not fully understood. Here we review the biochemical and physical processes involved in eliminating the products of light absorption from the photoreceptor outer segment, in recycling the released retinoid to its original isomeric form as 11-cis retinal, and in regenerating the visual pigment rhodopsin. Then we analyse the time-course of three aspects of human dark adaptation: the recovery of psychophysical threshold, the recovery of rod photoreceptor circulating current, and the regeneration of rhodopsin. We begin with normal human subjects, and then analyse the recovery in several retinal disorders, including Oguchi disease, vitamin A deficiency, fundus albipunctatus, Bothnia dystrophy and Stargardt disease. We review a large body of evidence showing that the time-course of human dark adaptation and pigment regeneration is determined by the local concentration of 11-cis retinal, and that after a large bleach the recovery is limited by the rate at which 11-cis retinal is delivered to opsin in the bleached rod outer segments. We present a mathematical model that successfully describes a wide range of results in human and other mammals. The theoretical analysis provides a simple means of estimating the relative concentration of free 11-cis retinal in the retina/RPE, in disorders exhibiting slowed dark adaptation, from analysis of psychophysical measurements of threshold recovery or from analysis of pigment regeneration kinetics.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness. The condition is associated with fundus discolouration and abnormally slow dark adaptation. Earlier studies suggested that the 48 kD protein S antigen may be involved in the recovery phase of light transduction. Previous cytogenetic and linkage studies have localised the S antigen gene (SAG) to chromosome 2q37.1. In the present study markers which map to distal chromosome 2q were typed in an inbred Oguchi pedigree. The segregation data obtained suggested that the affected subjects are homozygous by descent for a region between D2S172 and D2S345. An intragenic SAG polymorphism was homozygous in all affected people and a recombination event suggested that SAG maps proximal to D2S345. Collectively, these findings support the hypothesis that a defect in S antigen may be responsible for Oguchi disease.

PURPOSE. To determine the relationship between cone deactivation kinetics in patients with the enhanced S cone syndrome (ESCS) caused by mutations in NR2E3 and the immunoreactivity to G-protein– coupled receptor kinase 1 (GRK1) and GRK7. METHODS. Electroretinogram (ERG) photoresponses were used to investigate activation kinetics of cones with a model of cone phototransduction. Deactivation kinetics of cones after bright flashes was quantified with a paired-flash ERG paradigm. Immunocytochemistry was performed with antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue. RESULTS. Activation kinetics of long/middle-wavelength–sensitive (L/M) cone-mediated responses in patients with ESCS were similar to those of normal L/M cones. Activation kinetics of ESCS short-wavelength–sensitive (S) cones, when compared with normal L/M cone responses evoked by the same stimulus, were slower by an amount consistent with the expected differences in spectral sensitivities. After bright flashes chosen to evoke identical activation kinetics, ESCS S cones deactivated much more slowly than ESCS or normal L/M cones. Normal human retina revealed strongly labeled cone outer segments with anti-GRK1 and anti-GRK7. In an ESCS retina, outer segments positive for L/M opsin were strongly labeled with antiGRK1, whereas outer segments positive for S opsin showed no detectable GRK1 reactivity. GRK7 labeling was absent in all photoreceptors of the ESCS retina. CONCLUSIONS. The cone-dominant human retina resulting from NR2E3 mutations affords greater understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors. Normal deactivation kinetics in human L/M cones can occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is present but GRK1 is deficient in Oguchi disease. Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient. (Invest Ophthalmol Vis Sci. 2003;44:1268 –1274)

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.