Stationary Night Blindness Research Articles

A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration

BackgroundThe GNAT1 gene encodes the α subunit of the rod transducin protein, a key element in the rod phototransduction cascade. Variants in GNAT1 have been implicated in stationary night-blindness in...

Shortening of the rod outer segment in Oguchi disease

Dear Editor, Oguchi disease, characterized by stationary night blindness, is an inherited and non-progressive retinal disorder that affects the rods and causes impaired night vision [1]. Histologic findings have not been reported. We observed microstructural change of the retina in Oguchi disease using spectral domain optical coherence tomography (SD-OCT). A 31-year-old man had night blindness since childhood. His best-corrected visual acuity was 1.2 bilaterally. On ophthalmoscopic examination (Fig. 1), his fundus had a golden sheen reflex, except for the macular and perimacular areas. The macula had a normal red reflex, but the perimacular area was grayish bilaterally. A full-field ERG showed normal cone and flicker responses; the rod response was non-recordable. Multifocal ERG showed a normal response. The visual field was within normal limits on Goldmann perimetry. He was diagnosed with Oguchi disease. Oguchi disease has five subtypes depending on the location of the golden sheen reflex, i.e., the entire fundus, macula sparing, posterior fundus sparing, peripheral sparing, and far periphery sparing. The current case corresponds to the posterior fundus-sparing type. In a horizontal 6-mm scan across the fovea, the junction between photoreceptor inner and outer segment (IS/OS ) appeared normal in the macula within a 3-mm diameter; however, the distance between the IS/OS and retinal pigment epithelium (RPE) suddenly decreased, and the IS/ OS line was not identifiable in a 3-mm-wide perimacular ring, where the retina was attenuated because of decreased thickness of the outer nuclear layer (ONL). The IS/OS line emerged outside of the perimacular ring in the midperiphery, but the distance between the IS/OS and RPE was short, such that the two reflective lines fused into one broad reflective band in some areas. The midperipheral retinal thickness was normal. SD-OCT (Fig. 2) showed that the distance between the IS/OS line and RPE was short in the midperipheral fundus, which had a golden sheen. However, the IS/OS line appeared normal in the macula, where the fundus color was normal. The IS/OS line was not identifiable in the perimacular area, where the fundus was grayish, resembling an early change in retinitis pigmentosa. Since the IS/OS line indicates high reflectivity at the proximal portion of the photoreceptor outer segment, the decreased distance between the IS/OS and the RPE suggests shortening of the outer segment. OCT suggested that the lesion responsible for the golden sheen reflex appeared to be shortening of the rod outer segment. Full-field ERG showed a normal cone response and a non-recordable rod response. Since the cones were intact, the IS/OS appeared normal in the macula where the cones aggregate, and the fundus reflex was normal. It was noteworthy that the fundus reflex was grayish in the perimacular area where the IS/OS was not identifiable with attenuation of the ONL. The loss of the Graefes Arch Clin Exp Ophthalmol (2009) 247:1561–1563 DOI 10.1007/s00417-009-1114-6

Arrestin can act as a regulator of rhodopsin photochemistry

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.

GRK et arrestines : la piste thérapeutique ?

Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of beta-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests.

Biochemical Defects in 11-cis-Retinol Dehydrogenase Mutants Associated with Fundus Albipunctatus

Mutations in the gene encoding 11-cis-retinol dehydrogenase (RDH5; EC ) are associated with fundus albipunctatus, an autosomal recessive eye disease characterized by stationary night blindness and accumulation of white spots in the retina. In addition, some mutated alleles are associated with development of cone dystrophy, especially in elderly patients. The numbers of identified RDH5 mutations linked to fundus albipunctatus have increased considerably during recent years. In this work, we have characterized the biochemical and cell biological properties of 11 mutants of RDH5 to understand the molecular pathology of the disease. All RDH5 mutants showed decreased protein stability and subcellular mislocalization and, in most cases, loss of enzymatic activity in vitro and in vivo. Surprisingly, mutant A294P displays significant enzymatic activity. Cross-linking studies and molecular modeling showed that RDH5 is dimeric, and co-expression analyses of wild-type and mutated alleles showed that the mutated enzymes, in a trans-dominant-negative manner, influenced the in vivo enzymatic properties of functional variants of the enzyme, particularly the A294P mutant. Thus, under certain conditions, nonfunctional alleles act in a dominant-negative way on functional but relatively unstable mutated alleles. However, in heterozygous individuals carrying one wild-type allele, the disease is recessive, probably due to the stability of the wild-type enzyme.

Voltage-gated ion channels and hereditary disease.

By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.

The hereditary factor as a criterion for the classification of stationary congenital night blindness (author's transl)

The night-blind subject examined in 1952 by Schubert and Bornschein was reexamined electrophysiologically. All findings were unchanged. Normal a, d and g-waves in the ERG indicated undisturbed receptor function. Fast and slow oscillations of the EOG were normal. The subjective darkness-adaptation curve revealed minimal scotopic function after the 14th min of adaptation. The significance of clinical and electrophysiological findings for the classification of stationary congenital night blindness is discussed. The hereditary factor appears to be the most preferable criterion for the classification of stationary congenital night blindness.

Hereditary renal-retinal dysplasia.

Juvenile nephronophthisis and medullary cystic diseases are inherited kidney disorders leading to end stage uremia. As these diseases appear to be identical, they were grouped together in nephronophthisis-cystic renal medulla complex. Among its extrarenal manifestations, tapeto-retinal degeneration is the most frequent allied condition. This specific association of the renal and retinal conditions, suggesting a genetic background, is called hereditary renal-retinal dysplasia and is transmitted as an autosomal recessive trait. There are some variations in the type of the retinal degeneration in renal-retinal dysplasia and similar basic genetic mechanisms may results in Leber's congenital amaurosis, or retinitis pigmentosa, central retinal degeneration or stationary congenital night blindness. Pleiotropism seems to be responsible for the spectrum of these anomalies. Occasional expression in the heterozygous state by urinary concentrating disabilities or electroretinographic impairments were documented. The nature and pathogenesis of renal-retinal dysplasia remain a debated issue, but some evidence supports the possibility of an inborn error of metabolism causing the basic defects.

Advances in night vision technology. A pocketscope for patients with retinitis pigmentosa.

Thirteen patients with retinitis pigmentosa and two patients with stationary night blindness with myopia had marked improvements in visual thresholds under scotopic conditions with the aid of a Generation II night vision pocketscope. The symptom of night blindness could be effectively eliminated in these patients. All had visual acuities under scotopic conditions that were comparable to their best visual acuities under photopic conditions. Eleven of the 13 patients with retinitis pigmentosa reported thresholds lower than those obtained from normal dark-adapted subjects tested without the pocketscope. Patients with central fields greater than 10° reported that the pocketscope improved their mobility under scotopic conditions. Advantages of this Generation II pocketscope over a previously described Generation I device are discussed.

A Night Vision Device as an Aid for Patients With Retinitis Pigmentosa

Marked improvements in visual thresholds were observed in 14 patients with retinitis pigmentosa and in two patients with stationary night-blindness with myopia tested under scotopic conditions with a Generation I night vision device. All had visual acuities under scotopic conditions with the device that were comparable to their best visual acuities under photopic conditions. Psychophysical studies showed this device provided sufficient light amplification to allow cone function under dim scotopic conditions. Stimuli too dim to elicit a cone electroretinogram (ERG) without the device could elicit one with it. Results with this Generation I device as well as recent advances in microchannel technology (Generation II) suggest that a practical night vision device could be developed for patients with retinitis pigmentosa and other night-blinding conditions.