RARE DISEASE
Congenital stationary night blindness
Congenital stationary night blindness
Congenital stationary night blindness
Synonyms: Congenital essential nyctalopia
Synonyms: Congenital essential nyctalopia
Synonyms: Congenital essential nyctalopia
Drug discovery
0
drugs
With orphan designations
Overview
Congenital Stationary Night Blindness (CSNB) is a group of inherited retinal disorders marked by non-progressive nyctalopia, photophobia, and variable visual impairment. Caused by genetic mutations disrupting photoreceptor-bipolar cell signaling (e.g., NYX, CACNA1F, TRPM1), it is classified into complete (rod-dominated dysfunction) and incomplete (mixed rod-cone) subtypes. Diagnosis relies on electroretinography (ERG), clinical exam, and genetic testing. While stable, associated myopia, nystagmus, and strabismus require management [1][2][19].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
148 drug discovery papers about Congenital stationary night blindness, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
148 drug discovery papers about Congenital stationary night blindness, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-14 | The retinal light response is modulated by an mGluR5-mediated retrograde signal from ON-bipolar cells to photoreceptors
Abstract The ON visual pathway is initiated by the deactivation of mGluR6, coupled to the opening of TRPM1 channels in retinal ON-bipolar cell dendrites. Here, we show that a second metabotropic glutamate receptor, mGluR5, is localized with TRPM1 and mGluR6 in the dendrites of ON-bipolar cells. To examine the function of mGluR5, we performed electroretinogram (ERG) recordings and found that the amplitude of the b-wave, which is primarily a measure of ON-bipolar cell light-driven activity, is reduced in mGluR5 knock-out mice compared to wild type. In the mGluR5 -/- retina, we observed weaker mGluR6 immunofluorescence in the dendritic tips of ON-bipolar cells that could explain the smaller ERG b-wave. To observe the effect of mGluR5 without perturbing mGluR6 expression, wild type mice were injected with MTEP, an allosteric antagonist of mGluR5. MTEP increased the amplitude of the b-wave in response to dim stimuli and caused an inflection in the intensity-response plot for flashes in the mesopic range. In the brain, postsynaptic mGluR5 regulates presynaptic glutamate release via endocanabinoid-mediated retrograde signaling. Therefore, we tested the effect of the CB1 receptor antagonist, SR1417A, on the ERG and found that the b-wave was affected as by MTEP, including an inflection in the intensity-response. We further showed that the CB1 receptor agonist, ACEA, reversed the effects of MTEP. Together, our results indicate that mGluR5 plays a role in gain-control at the photoreceptor to ON-bipolar cell synapses, likely via an endocannabinoid-mediated retrograde feedback. Significance Statement Light-ON stimuli are transmitted from photoreceptors to ON-bipolar cells via three pathways, which are used under different light intensities, from dim to bright light. For each pathway, glutamate is the neurotransmitter released by rods and cones, and the postsynaptic role of the mGluR6-TRPM1 signaling cascade in ON-bipolar cells is well studied, with defects known to cause congenital stationary night blindness. We show here that mGluR5 is also present in ON-bipolar cell dendrites and regulates synaptic transmission between photoreceptors and ON-bipolar cells. In particular, we find that mGluR5 facilitates the transition between the different photoreceptor to ON-bipolar cell pathways via mGluR5-controlled retrograde release of endocannabinoids.
2025-09-12 | Natural course of refractive errors in early onset inherited retinal diseases.
Inherited retinal diseases (IRDs) are a leading cause of visual impairment in children and young adults. Individuals with IRDs have an increased prevalence of high refractive errors (REs). This study aims to characterise the natural progression of REs in patients with early onset IRDs and identify associations with specific IRDs and genes. Retrospective cohort study of patients diagnosed with IRD's up to the age of 10 years. Data collected included demographic information, IRD type, molecular analysis (when available), and cycloplegic REs from the first and last visits. A total of 199 patients (384 refractive measurements) were included in this study. Retinitis Pigmentosa (RP) and Achromatopsia were associated with high hypermetropia in early visits, with a decreasing RE trend over time. CNGA3, CNGB3, and CRB1 were associated with high hypermetropia, remaining high with time in CRB1. In contrast, Congenital Stationary Night Blindness (CSNB) and Blue Cone Monochromacy (BCM) demonstrated high myopia, worsening over time in CSNB, with an increasing rate in high myopia from 51.5% to 69.7% from first to last visit. Mean myopic progression in TRPM1-patients was 0.56 dioptres/year. In patients with early onset IRDs, refractive errors have a general tendency towards lower spherical equivalents with time. TRPM1-related myopia keeps progressing during the first decade of life, warranting regular screening and consideration of early myopia control interventions to mitigate the risk of myopia-related sight-threatening complications. High hypermetropia is common in RP, staying especially high in CRB1-related cases, highlighting the importance of early screening and refractive correction.
2025-07-01 | Divergent mechanisms of neural adaptation and instability in the mammalian retina.
Sensory circuits can exhibit remarkable resilience to disruption, often maintaining function through recruitment of compensatory mechanisms. In the mammalian retina, the balance between ON and OFF pathways that encode distinct luminance profiles is essential for processing visual information. How selective disruption of one input stream can trigger adaptive and/or compensatory measures in retinal output neurons is not fully understood. To determine how retinal output circuits can adapt to different degrees of input suppression, we genetically suppressed the ON pathway input in two models with partial (50%) and complete (100%) ON pathway blockade. We used single-cell electrophysiology to record intrinsic properties, synaptic inputs, and spike outputs of alpha retinal ganglion cell (RGC) types that serve as primary output channels. Complementary immunohistochemistry assessed structural changes in excitatory and inhibitory synaptic protein expression within individual RGCs. We found that 50% ON pathway suppression triggers adaptive scaling of excitatory synaptic proteins in ON and OFF RGCs that are aimed at preserving visual function. In contrast, complete suppression leads to maladaptive intrinsic alterations and cyclical instability in specific OFF-RGC types, impairing visual processing. We also observed luminance-level-dependent alterations in the OFF pathway output and contrast-encoding abilities after ON pathway suppression. Our findings reveal that the extent of input suppression determines whether compensatory mechanisms are beneficial or detrimental, offering new insights into retinal plasticity mechanisms. Uncovering these mechanisms expands our knowledge of sensory neuroplasticity, revealing potential therapeutic strategies for ameliorating dysfunction in disease conditions of ON pathway suppression, such as congenital stationary night blindness.
2024-08-07 | Joint Public Review: A non-conducting role of the Cav1.4 Ca2+ channel drives homeostatic plasticity at the cone photoreceptor synapse
In congenital stationary night blindness type 2 (CSNB2)—a disorder involving the Cav1.4 (L-type) Ca2+ channel—visual impairment is mild considering that Cav1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Cav1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Cav1.4. Surprisingly, Cav3 (T-type) Ca2+ currents were detected in cones of G369i KI mice and Cav1.4 KO mice but not in cones of wild-type mouse, ground squirrel, and macaque retina. Whereas Cav1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e., cone-mediated) visual behavior. Cone synapses, which fail to form in Cav1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Cav1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Cav3 channels maintain cone synaptic output provided that the nonconducting role of Cav1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.
2024-07-31 | Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study.
Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
gene therapies
2026-08-11 | StoneRounds Case: SR2212
StoneRounds Case SR2212 was diagnosed with Congenital Stationary Night Blindness likely caused by mutations in the gene: GRM6.
2026-07-19 | Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity.
Recombinant adeno-associated virus (rAAV) mediated gene therapy is an effective approach for targeting therapeutic genes to retinal photoreceptors. Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes that are part of a large, interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors. These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration. Because of the non-progressive and recessive nature of cCSNB, we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and cortical visual acuity. We used a mouse model of cCSNB caused by LRIT3 loss to evaluate the efficacy of a single subretinal injection of an rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity. We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity.
2026-07-10 | Therapeutic restoration of synaptic architecture, retinal and visual function, and prevention of retinal degeneration in a mouse model of retinal dystrophy.
Vision depends on the transfer of photoreceptor signals through the retina and then to many CNS visual nuclei. While the most common inherited retinal diseases (IRDs) involve defects in rod and/or cone function, another group (referred to as congenital stationary night blindness (CSNB)) results from defects in glutamate release from photoreceptors, or conversion of the glutamatergic signal in bipolar cells. One example results from mutations in the CACNA2D4 gene, which encodes a subunit of the voltage-gated calcium channel that is critical for glutamate release from both rod and cone photoreceptors. Mutations in CACNA2D4 result in a range of phenotypes in human patients, from incomplete CSNB to rod-cone dystrophy. In the CACNA2D4 knockout mouse ( α2δ4 -/- ), there is slow photoreceptor degeneration, the photoreceptor-to-bipolar cell synapse is disorganized, and the retina lacks scotopic and photopic full-field electroretinogram b-waves; this also results in low visual acuity. Using adult α2δ4 -/- mice, we show that recombinant adeno-associated virus (rAAV)-mediated gene therapy directed to rod photoreceptors prevents rod degeneration, restores synaptic organization, retinal function, and improves visual acuity under both light- and dark-adapted conditions. This rescue was maintained for up to 14 months post-treatment. Together, our results demonstrate that synaptic structure and function can be restored in the mature mouse retina in a model of complete synaptic disorganization. The results highlight the neuroprotective potential of targeting synaptic organizing proteins in retinal gene therapy.
2026-01-01 | Genomic Blueprints of Vision: A Comparative History of Rhodopsin Evolution and Phototransduction
Light is the fundamental signal for living entities as life on Earth is ultimately sustained by light energy. Many animals have evolved complex sensory mechanisms to utilize light cues for regulating homeostatic systems such as eyesight and the circadian clock. Organisms adapt to diverse lighting by modifying visual-pigment subtypes and their spectral tuning. These changes affect both color perception and dim-light vision. Through the lens of Comparative Genomics, evolution of opsins acts as a bridge between molecular genetics and ecological adaptation. Opsins are a diverse family of G-protein coupled receptors (GPCRs) that serve as the fundamental molecular interface between light and biological signaling. Rhodopsin is the 7-helical G-coupled receptor transmembrane protein. It also contains 11-cis-retinal, bound to the opsin protein, primarily absorbs light and responsible for scotopic vision in dim light conditions. This study compared Rhodopsin gene at gene sequence level, coding region and protein level among the twenty -six selected organisms from diverse groups including a set of model organisms such as Drosophila melanogaster , Danio rerio , Xenopus laevis , Rattus norvegicus , Gallus gallus , Macaca mulatta , Pan troglodyte and Homo sapiens . The sequence alignment studies show percentage similarities across the genomes and derive different functional annotations that exhibit a diverse role for Rhodopsin. Further the phylogenetic analysis shows how they evolved over the time. The comparative genomic analysis of rhodopsin across diverse organisms effectively demonstrates how evolutionary pressures shape genetic architecture to meet specific environmental demands. Rhodopsin plays a vital role in studying GPCRs vividly, mutations in rhodopsin lead to diseases like Retinitis Pigmentosa and Congenital Stationary Night Blindness which disrupts normal vision and also affect the circadian rhythm, dysregulation causing sleeping disorders. They serve as valuable biomarkers for the early retinal degeneration and detection of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
2026-01-01 | StoneRounds Case: SR680
StoneRounds Case SR680 was diagnosed with Congenital Stationary Night Blindness likely caused by mutations in the gene: TRPM1.
oligonucleotides
2024-01-11 | A Drosophila Model Reveals the Potential Role for mtt in Retinal Disease
Congenital stationary night blindness (CSNB) is a genetically heterogeneous inherited retinal disorder, caused by over 300 mutations in 17 different genes. While there are numerous fly models available for simulating ocular diseases, most are focused on mimicking retinitis pigmentosa (RP), with animal models specifically addressing CSNB limited to mammals. Here, we present a CSNB fly model associated with the mtt gene, utilizing RNA interference (RNAi) to silence the mtt gene in fly eyes (homologous to the mammalian GRM6 gene) and construct a CSNB model. Through this approach, we observed significant defects in the eye structure and function upon reducing mtt expression in fly eyes. This manifested as disruptions in the compound eye lens structure and reduced sensitivity to light responses. These results suggest a critical role for mtt in the function of fly adult eyes. Interestingly, we found that the mtt gene is not expressed in the photoreceptor neurons of adult flies but is localized to the inner lamina neurons. In summary, these results underscore the crucial involvement of mtt in fly retinal function, providing a framework for understanding the pathogenic mechanisms of CSNB and facilitating research into potential therapeutic interventions.
2023-03-10 | Shedding light on myopia by studying complete congenital stationary night blindness.
Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare progressive and stationary inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in a variety of biological processes including eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signaling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON-bipolar cell signal transmission defect and is also associated with high myopia. Thus, it represents also an interesting model to identify myopia-related genes, as well as disease mechanisms. While the origin of night blindness is molecularly well established, further research is needed to elucidate the mechanisms of myopia development in subjects with cCSNB. Using whole transcriptome analysis on three different mouse models of cCSNB (in Gpr179-/-, Lrit3-/- and Grm6-/-), we identified novel actors of the retinal signaling cascade, which are also novel candidate genes for myopia. Meta-analysis of our transcriptomic data with published transcriptomic databases and genome-wide association studies from myopia cases led us to propose new biological/cellular processes/mechanisms potentially at the origin of myopia in cCSNB subjects. The results provide a foundation to guide the development of pharmacological myopia therapies.
2019-08-20 | Visual arrestin modulates gene expression in the retinal pigment epithelium: Implications for homeostasis in the retina
The retinal pigment epithelium (RPE) is essential for maintaining retinal homeostasis by removing and recycling photoreceptor outer segment (POS) in membranes. It also produces and secretes growth factors involved in retinal homeostasis. Arrestin 1 (ARR1) is specifically expressed in photoreceptors (PRs) and a vital molecule for keeping visual cycle between PRs and RPE. In the present study, we showed the expression of ARR1 was decreased by form-deprivation (FD) in retina of rat. The ARR1 was detected in the RPE of the controls but not in the RPE of FD, which indicates RPE phagocytes POS containing ARR1. Furthermore, we overexpressed ARR1 in cultured human RPE and revealed the ARR1 upregulates bFGF expression and downregulates TGF-β1, -β2 and bone morphogenetic protein-2 (BMP-2). The upregulation of bFGF by ARR1 directly works for PR survival and the downregulation of TGF-βs by ARR1 inhibits epithelial mesenchymal transition (EMT) of RPE, which is the underlying mechanism of keeping retinal homeostasis. Our results also indicate the regulation of ARR1 expression in RPE might become a novel therapeutic option for various ocular diseases.
2016-04-18 | Characterization of Ribozymes Targeting a Congenital Night Blindness Mutation in Rhodopsin Mutation.
The G90D mutation in the rhodopsin gene leads to autosomal dominant congenital stationary night blindness (CSNB) in patients. This occurs because the G90D mutant protein cannot efficiently bind chromophore and is constitutively active. To combat this mutation, we designed and characterized two different hammerhead ribozymes to cleave G90D transcript. In vitro testing showed that the G90D1 ribozyme efficiently and specifically cleaved the mutant transcript while G90D2 cleaved both WT and mutant transcript. AAV-mediated delivery of G90D1 under the control of the mouse opsin promoter (MOP500) to G90D transgenic eyes showed that the ribozyme partially retarded the functional degeneration (as measured by electroretinography [ERG]) associated with this mutation. These results suggest that with additional optimization, ribozymes may be a useful part of the gene therapy knockdown strategy for dominant retinal disease.
2015-09-23 | The impact of microRNA gene regulation on the survival and function of mature cell types in the eye
MicroRNAs (miRNAs) regulate multiple genes, often within the same pathway, fine-tuning expression of key factors and stabilizing gene networks against aberrant fluctuations. The demanding physiologic functions of photoreceptor cells and the retinal pigmented epithelium necessitate precise gene regulation to maintain their homeostasis and function, thus rendering these postmitotic cells vulnerable to premature death in retinal degenerative disorders. Recent studies of the physiologic impact of miRNAs in these cells clearly demonstrate that miRNAs are an essential component of that gene regulation. These important advances provide the foundation for future exploration of miRNA-regulated gene networks in the eye to facilitate the development of miRNA-targeted therapeutics to combat blinding diseases.
proteins
2026-01-01 | G-protein activation of the dark-state conformation of the visual G protein-coupled receptor rhodopsin by releasing critical structural constraints
G protein–coupled receptors (GPCRs) operate through the binding and activation of heterotrimeric G proteins. Ligand interaction drives the receptor’s transition from an inactive to an active state, ultimately triggering G-protein activation and downstream signal transduction. The visual GPCR rhodopsin contains the chromophore 11-cis-retinal, which is covalently bound and functions as an inverse agonist, maintaining very low basal activity in the absence of light. Disruption of this basal receptor activity can lead to physiological consequences associated with retinal diseases such as congenital stationary night blindness and retinitis pigmentosa. Here, we describe a functional dark-state rhodopsin generated through engineered double and triple mutations at three well-defined structural microswitches that regulate the conformational stability of the dark ground-state: i) T942.61I, located near the protonated Schiff base linkage environment and linked to congenital stationary night blindness; ii) M2576.40Y positioned close to the tyrosine cluster (Y2235.58 and Y3067.53 of the NPxxY motif); and iii) E1343.49 within the conserved (D/E)RY motif, which participates in the so-called ionic lock involving R1353.50 and E2476.30. Characterization of these mutant rhodopsins provides additional insights into the structural basis of the inactive-to-active conformational transition in important functional domains and emphasizes rhodopsin conformational flexibility.
2025-09-26 | Domain-specific functions of LRIT3 in synaptic assembly and retinal signal transmission.
LRIT3 is a leucine-rich repeat (LRR) protein that is expressed in the retina, and its absence causes complete congenital stationary night blindness (cCSNB), a genetically diverse disorder characterized by impaired low-light vision, myopia, and nystagmus. LRIT3 is expressed in rod and cone photoreceptors, and it trans-synaptically organizes the assembly of the glutamate signaling complex, the signalplex, on depolarizing bipolar cells (DBCs). LRIT3 is a single-pass membrane protein with extracellular LRR, IG, and FN3 domains. The mechanism by which LRIT3 controls postsynaptic receptor organization remains unknown. We address this by using rAAV to express deletion constructs in LRIT3 knockout retinas and examining LRIT3 trafficking, as well as the structural and functional recovery of the signalplex in DBCs. We show the LRR domain is required for trafficking LRIT3 to the synapse in cones, but not rod photoreceptors, although it is needed for reassembly and function of the rod BC signalplex. Neither the IG nor the FN3 domain is needed for synaptic localization of LRIT3. However, the IG domain is required for the localization of TRPM1 to the signalplex and thus function. The FN3 domain is not necessary for either DBC signalplex assembly or function. Our data demonstrates that the LRR and IG domains of LRIT3 are crucial for TRPM1 localization and retinal function, with the LRR domain playing a key role in the differential function of LRIT3 at rod and cone synapses. Notably, our results show that restoring Nyctalopin localization to the DBC signalplex alone is insufficient to restore TRPM1 expression. Based on our findings, we propose a model in which the LRR domain trans-synaptically binds with Nyctalopin, while the IG domain interacts with TRPM1.
2022-03-01 | Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1
Phosphodiesterase 6 (PDE6) is a key effector enzyme in vertebrate phototransduction, and its maturation and function are known to critically depend on a specialized chaperone, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1). Defects in PDE6 and AIPL1 underlie several severe retinal diseases, including retinitis pigmentosa and Leber congenital amaurosis. Here, we characterize the complex of AIPL1 with HSP90 and demonstrate its essential role in promoting the functional conformation of nascent PDE6. Our analysis suggests that AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2, with the tetratricopeptide repeat domain and the tetratricopeptide repeat helix 7 extension of AIPL1 being the main contributors to the AIPL1/HSP90 interface. We demonstrate that mutations of these determinants markedly diminished both the affinity of AIPL1 for HSP90 and the ability of AIPL1 to cochaperone the maturation of PDE6 in a heterologous expression system. In addition, the FK506-binding protein (FKBP) domain of AIPL1 encloses a unique prenyl-binding site that anchors AIPL1 to posttranslational lipid modifications of PDE6. A mouse model with rod PDE6 lacking farnesylation of its PDE6A subunit revealed normal expression, trafficking, and signaling of the enzyme. Furthermore, AIPL1 was unexpectedly capable of inducing the maturation of unprenylated cone PDE6C, whereas mutant AIPL1 deficient in prenyl binding competently cochaperoned prenylated PDE6C. Thus, we conclude neither sequestration of the prenyl modifications is required for PDE6 maturation to proceed, nor is the FKBP-lipid interaction involved in the conformational switch of the enzyme into the functional state.
2017-08-08 | Retinoschisin Facilitates the Function of L-Type Voltage-Gated Calcium Channels
Modulation of ion channels by extracellular proteins plays critical roles in shaping synaptic plasticity. Retinoschisin (RS1) is an extracellular adhesive protein secreted from photoreceptors and bipolar cells, and it plays an important role during retinal development, as well as in maintaining the stability of retinal layers. RS1 is known to form homologous octamers and interact with molecules on the plasma membrane including phosphatidylserine, sodium-potassium exchanger complex, and L-type voltage-gated calcium channels (LTCCs). However, how this physical interaction between RS1 and ion channels might affect the channel gating properties is unclear. In retinal photoreceptors, two major LTCCs are Cav1.3 (α1D) and Cav1.4 (α1F) with distinct biophysical properties, functions and distributions. Cav1.3 is distributed from the inner segment (IS) to the synaptic terminal and is responsible for calcium influx to the photoreceptors and overall calcium homeostasis. Cav1.4 is only expressed at the synaptic terminal and is responsible for neurotransmitter release. Mutations of the gene encoding Cav1.4 cause X-linked incomplete congenital stationary night blindness type 2 (CSNB2), while null mutations of Cav1.3 cause a mild decrease of retinal light responses in mice. Even though RS1 is known to maintain retinal architecture, in this study, we present that RS1 interacts with both Cav1.3 and Cav1.4 and regulates their activations. RS1 was able to co-immunoprecipitate with Cav1.3 and Cav1.4 from porcine retinas, and it increased the LTCC currents and facilitated voltage-dependent activation in HEK cells co-transfected with RS1 and Cav1.3 or Cav1.4, thus providing evidence of a functional interaction between RS1 and LTCCs. The interaction between RS1 and Cav1.3 did not change the calcium-dependent inactivation of Cav1.3. In mice lacking RS1, the expression of Cav1.3 and Cav1.4 in the retina decreased, while in mice with Cav1.4 deletion, the retinal level of RS1 decreased. These results provide important evidence that RS1 is not only an adhesive protein promoting cell-cell adhesion, it is essential for anchoring other membrane proteins including ion channels and enhancing their function in the retina.
2016-06-08 | Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client
Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory Pγ-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and Pγ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants. Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory Pγ-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and Pγ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants.
other
2024-08-07 | Anti-TRPM1 autoantibody-positive unilateral melanoma associated retinopathy (MAR) triggered by immunotherapy recapitulates functional and structural details of TRPM1-associated congenital stationary night blindness.
To describe the retinal phenotype of an unusual case of anti-TRPM1 autoantibody-positive unilateral melanoma-associated retinopathy (MAR) triggered by nivolumab therapy and compare with the phenotype of TRPM1-associated Congenital Stationary Night Blindness (TRPM1-CSNB). Unilateral MAR was diagnosed 3 months after starting nivolumab therapy for consolidation of a successfully treated melanoma. Retinal autoantibodies against TRPM1 were identified. ffERG, microperimetry and static chromatic perimetry confirmed unilateral ON-Bipolar Cell (ON-BPC) dysfunction and central rod sensitivity losses in the left eye; the contralateral eye was normal. There was borderline ganglion cell (GCL) and inner nuclear layer (INL) thinning, but a significantly thinner inner plexiform layer (IPL) in the affected compared to the unaffected eye. Longitudinal reflectivity profiles (LRPs) demonstrated an abnormal inner plexiform layer (IPL) lamination in the involved eye. Nearly identical changes were documented in two cases of TRMP1-cCSNB and in a case of anti-TRPM1 autoantibody-negative MAR. The functional changes partially recovered with discontinuation of the medication without added immunosuppression. Comparisons between the affected and unaffected eye in this unilateral MAR case revealed inner retinal abnormalities and abnormal lamination of the IPL associated with the classical retina-wide ON-BPC dysfunction, and localized central rod-mediated sensitivity losses. A nearly identical structural phenotype in two cases of cCSNB and a case of anti-TRPM1 autoantibody-negative MAR supports a specific structural-functional phenotype for these conditions with ON-BPC dysfunction.
small molecules
2025-11-14 | The retinal light response is modulated by an mGluR5-mediated retrograde signal from ON-bipolar cells to photoreceptors
Abstract The ON visual pathway is initiated by the deactivation of mGluR6, coupled to the opening of TRPM1 channels in retinal ON-bipolar cell dendrites. Here, we show that a second metabotropic glutamate receptor, mGluR5, is localized with TRPM1 and mGluR6 in the dendrites of ON-bipolar cells. To examine the function of mGluR5, we performed electroretinogram (ERG) recordings and found that the amplitude of the b-wave, which is primarily a measure of ON-bipolar cell light-driven activity, is reduced in mGluR5 knock-out mice compared to wild type. In the mGluR5 -/- retina, we observed weaker mGluR6 immunofluorescence in the dendritic tips of ON-bipolar cells that could explain the smaller ERG b-wave. To observe the effect of mGluR5 without perturbing mGluR6 expression, wild type mice were injected with MTEP, an allosteric antagonist of mGluR5. MTEP increased the amplitude of the b-wave in response to dim stimuli and caused an inflection in the intensity-response plot for flashes in the mesopic range. In the brain, postsynaptic mGluR5 regulates presynaptic glutamate release via endocanabinoid-mediated retrograde signaling. Therefore, we tested the effect of the CB1 receptor antagonist, SR1417A, on the ERG and found that the b-wave was affected as by MTEP, including an inflection in the intensity-response. We further showed that the CB1 receptor agonist, ACEA, reversed the effects of MTEP. Together, our results indicate that mGluR5 plays a role in gain-control at the photoreceptor to ON-bipolar cell synapses, likely via an endocannabinoid-mediated retrograde feedback. Significance Statement Light-ON stimuli are transmitted from photoreceptors to ON-bipolar cells via three pathways, which are used under different light intensities, from dim to bright light. For each pathway, glutamate is the neurotransmitter released by rods and cones, and the postsynaptic role of the mGluR6-TRPM1 signaling cascade in ON-bipolar cells is well studied, with defects known to cause congenital stationary night blindness. We show here that mGluR5 is also present in ON-bipolar cell dendrites and regulates synaptic transmission between photoreceptors and ON-bipolar cells. In particular, we find that mGluR5 facilitates the transition between the different photoreceptor to ON-bipolar cell pathways via mGluR5-controlled retrograde release of endocannabinoids.
2025-09-12 | Natural course of refractive errors in early onset inherited retinal diseases.
Inherited retinal diseases (IRDs) are a leading cause of visual impairment in children and young adults. Individuals with IRDs have an increased prevalence of high refractive errors (REs). This study aims to characterise the natural progression of REs in patients with early onset IRDs and identify associations with specific IRDs and genes. Retrospective cohort study of patients diagnosed with IRD's up to the age of 10 years. Data collected included demographic information, IRD type, molecular analysis (when available), and cycloplegic REs from the first and last visits. A total of 199 patients (384 refractive measurements) were included in this study. Retinitis Pigmentosa (RP) and Achromatopsia were associated with high hypermetropia in early visits, with a decreasing RE trend over time. CNGA3, CNGB3, and CRB1 were associated with high hypermetropia, remaining high with time in CRB1. In contrast, Congenital Stationary Night Blindness (CSNB) and Blue Cone Monochromacy (BCM) demonstrated high myopia, worsening over time in CSNB, with an increasing rate in high myopia from 51.5% to 69.7% from first to last visit. Mean myopic progression in TRPM1-patients was 0.56 dioptres/year. In patients with early onset IRDs, refractive errors have a general tendency towards lower spherical equivalents with time. TRPM1-related myopia keeps progressing during the first decade of life, warranting regular screening and consideration of early myopia control interventions to mitigate the risk of myopia-related sight-threatening complications. High hypermetropia is common in RP, staying especially high in CRB1-related cases, highlighting the importance of early screening and refractive correction.
2025-07-01 | Divergent mechanisms of neural adaptation and instability in the mammalian retina.
Sensory circuits can exhibit remarkable resilience to disruption, often maintaining function through recruitment of compensatory mechanisms. In the mammalian retina, the balance between ON and OFF pathways that encode distinct luminance profiles is essential for processing visual information. How selective disruption of one input stream can trigger adaptive and/or compensatory measures in retinal output neurons is not fully understood. To determine how retinal output circuits can adapt to different degrees of input suppression, we genetically suppressed the ON pathway input in two models with partial (50%) and complete (100%) ON pathway blockade. We used single-cell electrophysiology to record intrinsic properties, synaptic inputs, and spike outputs of alpha retinal ganglion cell (RGC) types that serve as primary output channels. Complementary immunohistochemistry assessed structural changes in excitatory and inhibitory synaptic protein expression within individual RGCs. We found that 50% ON pathway suppression triggers adaptive scaling of excitatory synaptic proteins in ON and OFF RGCs that are aimed at preserving visual function. In contrast, complete suppression leads to maladaptive intrinsic alterations and cyclical instability in specific OFF-RGC types, impairing visual processing. We also observed luminance-level-dependent alterations in the OFF pathway output and contrast-encoding abilities after ON pathway suppression. Our findings reveal that the extent of input suppression determines whether compensatory mechanisms are beneficial or detrimental, offering new insights into retinal plasticity mechanisms. Uncovering these mechanisms expands our knowledge of sensory neuroplasticity, revealing potential therapeutic strategies for ameliorating dysfunction in disease conditions of ON pathway suppression, such as congenital stationary night blindness.
2024-08-07 | Joint Public Review: A non-conducting role of the Cav1.4 Ca2+ channel drives homeostatic plasticity at the cone photoreceptor synapse
In congenital stationary night blindness type 2 (CSNB2)—a disorder involving the Cav1.4 (L-type) Ca2+ channel—visual impairment is mild considering that Cav1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Cav1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Cav1.4. Surprisingly, Cav3 (T-type) Ca2+ currents were detected in cones of G369i KI mice and Cav1.4 KO mice but not in cones of wild-type mouse, ground squirrel, and macaque retina. Whereas Cav1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e., cone-mediated) visual behavior. Cone synapses, which fail to form in Cav1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Cav1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Cav3 channels maintain cone synaptic output provided that the nonconducting role of Cav1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.
2024-07-31 | Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study.
Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
gene therapies
2026-08-11 | StoneRounds Case: SR2212
StoneRounds Case SR2212 was diagnosed with Congenital Stationary Night Blindness likely caused by mutations in the gene: GRM6.
2026-07-19 | Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity.
Recombinant adeno-associated virus (rAAV) mediated gene therapy is an effective approach for targeting therapeutic genes to retinal photoreceptors. Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes that are part of a large, interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors. These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration. Because of the non-progressive and recessive nature of cCSNB, we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and cortical visual acuity. We used a mouse model of cCSNB caused by LRIT3 loss to evaluate the efficacy of a single subretinal injection of an rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity. We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity.
2026-07-10 | Therapeutic restoration of synaptic architecture, retinal and visual function, and prevention of retinal degeneration in a mouse model of retinal dystrophy.
Vision depends on the transfer of photoreceptor signals through the retina and then to many CNS visual nuclei. While the most common inherited retinal diseases (IRDs) involve defects in rod and/or cone function, another group (referred to as congenital stationary night blindness (CSNB)) results from defects in glutamate release from photoreceptors, or conversion of the glutamatergic signal in bipolar cells. One example results from mutations in the CACNA2D4 gene, which encodes a subunit of the voltage-gated calcium channel that is critical for glutamate release from both rod and cone photoreceptors. Mutations in CACNA2D4 result in a range of phenotypes in human patients, from incomplete CSNB to rod-cone dystrophy. In the CACNA2D4 knockout mouse ( α2δ4 -/- ), there is slow photoreceptor degeneration, the photoreceptor-to-bipolar cell synapse is disorganized, and the retina lacks scotopic and photopic full-field electroretinogram b-waves; this also results in low visual acuity. Using adult α2δ4 -/- mice, we show that recombinant adeno-associated virus (rAAV)-mediated gene therapy directed to rod photoreceptors prevents rod degeneration, restores synaptic organization, retinal function, and improves visual acuity under both light- and dark-adapted conditions. This rescue was maintained for up to 14 months post-treatment. Together, our results demonstrate that synaptic structure and function can be restored in the mature mouse retina in a model of complete synaptic disorganization. The results highlight the neuroprotective potential of targeting synaptic organizing proteins in retinal gene therapy.
2026-01-01 | Genomic Blueprints of Vision: A Comparative History of Rhodopsin Evolution and Phototransduction
Light is the fundamental signal for living entities as life on Earth is ultimately sustained by light energy. Many animals have evolved complex sensory mechanisms to utilize light cues for regulating homeostatic systems such as eyesight and the circadian clock. Organisms adapt to diverse lighting by modifying visual-pigment subtypes and their spectral tuning. These changes affect both color perception and dim-light vision. Through the lens of Comparative Genomics, evolution of opsins acts as a bridge between molecular genetics and ecological adaptation. Opsins are a diverse family of G-protein coupled receptors (GPCRs) that serve as the fundamental molecular interface between light and biological signaling. Rhodopsin is the 7-helical G-coupled receptor transmembrane protein. It also contains 11-cis-retinal, bound to the opsin protein, primarily absorbs light and responsible for scotopic vision in dim light conditions. This study compared Rhodopsin gene at gene sequence level, coding region and protein level among the twenty -six selected organisms from diverse groups including a set of model organisms such as Drosophila melanogaster , Danio rerio , Xenopus laevis , Rattus norvegicus , Gallus gallus , Macaca mulatta , Pan troglodyte and Homo sapiens . The sequence alignment studies show percentage similarities across the genomes and derive different functional annotations that exhibit a diverse role for Rhodopsin. Further the phylogenetic analysis shows how they evolved over the time. The comparative genomic analysis of rhodopsin across diverse organisms effectively demonstrates how evolutionary pressures shape genetic architecture to meet specific environmental demands. Rhodopsin plays a vital role in studying GPCRs vividly, mutations in rhodopsin lead to diseases like Retinitis Pigmentosa and Congenital Stationary Night Blindness which disrupts normal vision and also affect the circadian rhythm, dysregulation causing sleeping disorders. They serve as valuable biomarkers for the early retinal degeneration and detection of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
2026-01-01 | StoneRounds Case: SR680
StoneRounds Case SR680 was diagnosed with Congenital Stationary Night Blindness likely caused by mutations in the gene: TRPM1.
oligonucleotides
2024-01-11 | A Drosophila Model Reveals the Potential Role for mtt in Retinal Disease
Congenital stationary night blindness (CSNB) is a genetically heterogeneous inherited retinal disorder, caused by over 300 mutations in 17 different genes. While there are numerous fly models available for simulating ocular diseases, most are focused on mimicking retinitis pigmentosa (RP), with animal models specifically addressing CSNB limited to mammals. Here, we present a CSNB fly model associated with the mtt gene, utilizing RNA interference (RNAi) to silence the mtt gene in fly eyes (homologous to the mammalian GRM6 gene) and construct a CSNB model. Through this approach, we observed significant defects in the eye structure and function upon reducing mtt expression in fly eyes. This manifested as disruptions in the compound eye lens structure and reduced sensitivity to light responses. These results suggest a critical role for mtt in the function of fly adult eyes. Interestingly, we found that the mtt gene is not expressed in the photoreceptor neurons of adult flies but is localized to the inner lamina neurons. In summary, these results underscore the crucial involvement of mtt in fly retinal function, providing a framework for understanding the pathogenic mechanisms of CSNB and facilitating research into potential therapeutic interventions.
2023-03-10 | Shedding light on myopia by studying complete congenital stationary night blindness.
Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare progressive and stationary inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in a variety of biological processes including eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signaling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON-bipolar cell signal transmission defect and is also associated with high myopia. Thus, it represents also an interesting model to identify myopia-related genes, as well as disease mechanisms. While the origin of night blindness is molecularly well established, further research is needed to elucidate the mechanisms of myopia development in subjects with cCSNB. Using whole transcriptome analysis on three different mouse models of cCSNB (in Gpr179-/-, Lrit3-/- and Grm6-/-), we identified novel actors of the retinal signaling cascade, which are also novel candidate genes for myopia. Meta-analysis of our transcriptomic data with published transcriptomic databases and genome-wide association studies from myopia cases led us to propose new biological/cellular processes/mechanisms potentially at the origin of myopia in cCSNB subjects. The results provide a foundation to guide the development of pharmacological myopia therapies.
2019-08-20 | Visual arrestin modulates gene expression in the retinal pigment epithelium: Implications for homeostasis in the retina
The retinal pigment epithelium (RPE) is essential for maintaining retinal homeostasis by removing and recycling photoreceptor outer segment (POS) in membranes. It also produces and secretes growth factors involved in retinal homeostasis. Arrestin 1 (ARR1) is specifically expressed in photoreceptors (PRs) and a vital molecule for keeping visual cycle between PRs and RPE. In the present study, we showed the expression of ARR1 was decreased by form-deprivation (FD) in retina of rat. The ARR1 was detected in the RPE of the controls but not in the RPE of FD, which indicates RPE phagocytes POS containing ARR1. Furthermore, we overexpressed ARR1 in cultured human RPE and revealed the ARR1 upregulates bFGF expression and downregulates TGF-β1, -β2 and bone morphogenetic protein-2 (BMP-2). The upregulation of bFGF by ARR1 directly works for PR survival and the downregulation of TGF-βs by ARR1 inhibits epithelial mesenchymal transition (EMT) of RPE, which is the underlying mechanism of keeping retinal homeostasis. Our results also indicate the regulation of ARR1 expression in RPE might become a novel therapeutic option for various ocular diseases.
2016-04-18 | Characterization of Ribozymes Targeting a Congenital Night Blindness Mutation in Rhodopsin Mutation.
The G90D mutation in the rhodopsin gene leads to autosomal dominant congenital stationary night blindness (CSNB) in patients. This occurs because the G90D mutant protein cannot efficiently bind chromophore and is constitutively active. To combat this mutation, we designed and characterized two different hammerhead ribozymes to cleave G90D transcript. In vitro testing showed that the G90D1 ribozyme efficiently and specifically cleaved the mutant transcript while G90D2 cleaved both WT and mutant transcript. AAV-mediated delivery of G90D1 under the control of the mouse opsin promoter (MOP500) to G90D transgenic eyes showed that the ribozyme partially retarded the functional degeneration (as measured by electroretinography [ERG]) associated with this mutation. These results suggest that with additional optimization, ribozymes may be a useful part of the gene therapy knockdown strategy for dominant retinal disease.
2015-09-23 | The impact of microRNA gene regulation on the survival and function of mature cell types in the eye
MicroRNAs (miRNAs) regulate multiple genes, often within the same pathway, fine-tuning expression of key factors and stabilizing gene networks against aberrant fluctuations. The demanding physiologic functions of photoreceptor cells and the retinal pigmented epithelium necessitate precise gene regulation to maintain their homeostasis and function, thus rendering these postmitotic cells vulnerable to premature death in retinal degenerative disorders. Recent studies of the physiologic impact of miRNAs in these cells clearly demonstrate that miRNAs are an essential component of that gene regulation. These important advances provide the foundation for future exploration of miRNA-regulated gene networks in the eye to facilitate the development of miRNA-targeted therapeutics to combat blinding diseases.
proteins
2026-01-01 | G-protein activation of the dark-state conformation of the visual G protein-coupled receptor rhodopsin by releasing critical structural constraints
G protein–coupled receptors (GPCRs) operate through the binding and activation of heterotrimeric G proteins. Ligand interaction drives the receptor’s transition from an inactive to an active state, ultimately triggering G-protein activation and downstream signal transduction. The visual GPCR rhodopsin contains the chromophore 11-cis-retinal, which is covalently bound and functions as an inverse agonist, maintaining very low basal activity in the absence of light. Disruption of this basal receptor activity can lead to physiological consequences associated with retinal diseases such as congenital stationary night blindness and retinitis pigmentosa. Here, we describe a functional dark-state rhodopsin generated through engineered double and triple mutations at three well-defined structural microswitches that regulate the conformational stability of the dark ground-state: i) T942.61I, located near the protonated Schiff base linkage environment and linked to congenital stationary night blindness; ii) M2576.40Y positioned close to the tyrosine cluster (Y2235.58 and Y3067.53 of the NPxxY motif); and iii) E1343.49 within the conserved (D/E)RY motif, which participates in the so-called ionic lock involving R1353.50 and E2476.30. Characterization of these mutant rhodopsins provides additional insights into the structural basis of the inactive-to-active conformational transition in important functional domains and emphasizes rhodopsin conformational flexibility.
2025-09-26 | Domain-specific functions of LRIT3 in synaptic assembly and retinal signal transmission.
LRIT3 is a leucine-rich repeat (LRR) protein that is expressed in the retina, and its absence causes complete congenital stationary night blindness (cCSNB), a genetically diverse disorder characterized by impaired low-light vision, myopia, and nystagmus. LRIT3 is expressed in rod and cone photoreceptors, and it trans-synaptically organizes the assembly of the glutamate signaling complex, the signalplex, on depolarizing bipolar cells (DBCs). LRIT3 is a single-pass membrane protein with extracellular LRR, IG, and FN3 domains. The mechanism by which LRIT3 controls postsynaptic receptor organization remains unknown. We address this by using rAAV to express deletion constructs in LRIT3 knockout retinas and examining LRIT3 trafficking, as well as the structural and functional recovery of the signalplex in DBCs. We show the LRR domain is required for trafficking LRIT3 to the synapse in cones, but not rod photoreceptors, although it is needed for reassembly and function of the rod BC signalplex. Neither the IG nor the FN3 domain is needed for synaptic localization of LRIT3. However, the IG domain is required for the localization of TRPM1 to the signalplex and thus function. The FN3 domain is not necessary for either DBC signalplex assembly or function. Our data demonstrates that the LRR and IG domains of LRIT3 are crucial for TRPM1 localization and retinal function, with the LRR domain playing a key role in the differential function of LRIT3 at rod and cone synapses. Notably, our results show that restoring Nyctalopin localization to the DBC signalplex alone is insufficient to restore TRPM1 expression. Based on our findings, we propose a model in which the LRR domain trans-synaptically binds with Nyctalopin, while the IG domain interacts with TRPM1.
2022-03-01 | Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1
Phosphodiesterase 6 (PDE6) is a key effector enzyme in vertebrate phototransduction, and its maturation and function are known to critically depend on a specialized chaperone, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1). Defects in PDE6 and AIPL1 underlie several severe retinal diseases, including retinitis pigmentosa and Leber congenital amaurosis. Here, we characterize the complex of AIPL1 with HSP90 and demonstrate its essential role in promoting the functional conformation of nascent PDE6. Our analysis suggests that AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2, with the tetratricopeptide repeat domain and the tetratricopeptide repeat helix 7 extension of AIPL1 being the main contributors to the AIPL1/HSP90 interface. We demonstrate that mutations of these determinants markedly diminished both the affinity of AIPL1 for HSP90 and the ability of AIPL1 to cochaperone the maturation of PDE6 in a heterologous expression system. In addition, the FK506-binding protein (FKBP) domain of AIPL1 encloses a unique prenyl-binding site that anchors AIPL1 to posttranslational lipid modifications of PDE6. A mouse model with rod PDE6 lacking farnesylation of its PDE6A subunit revealed normal expression, trafficking, and signaling of the enzyme. Furthermore, AIPL1 was unexpectedly capable of inducing the maturation of unprenylated cone PDE6C, whereas mutant AIPL1 deficient in prenyl binding competently cochaperoned prenylated PDE6C. Thus, we conclude neither sequestration of the prenyl modifications is required for PDE6 maturation to proceed, nor is the FKBP-lipid interaction involved in the conformational switch of the enzyme into the functional state.
2017-08-08 | Retinoschisin Facilitates the Function of L-Type Voltage-Gated Calcium Channels
Modulation of ion channels by extracellular proteins plays critical roles in shaping synaptic plasticity. Retinoschisin (RS1) is an extracellular adhesive protein secreted from photoreceptors and bipolar cells, and it plays an important role during retinal development, as well as in maintaining the stability of retinal layers. RS1 is known to form homologous octamers and interact with molecules on the plasma membrane including phosphatidylserine, sodium-potassium exchanger complex, and L-type voltage-gated calcium channels (LTCCs). However, how this physical interaction between RS1 and ion channels might affect the channel gating properties is unclear. In retinal photoreceptors, two major LTCCs are Cav1.3 (α1D) and Cav1.4 (α1F) with distinct biophysical properties, functions and distributions. Cav1.3 is distributed from the inner segment (IS) to the synaptic terminal and is responsible for calcium influx to the photoreceptors and overall calcium homeostasis. Cav1.4 is only expressed at the synaptic terminal and is responsible for neurotransmitter release. Mutations of the gene encoding Cav1.4 cause X-linked incomplete congenital stationary night blindness type 2 (CSNB2), while null mutations of Cav1.3 cause a mild decrease of retinal light responses in mice. Even though RS1 is known to maintain retinal architecture, in this study, we present that RS1 interacts with both Cav1.3 and Cav1.4 and regulates their activations. RS1 was able to co-immunoprecipitate with Cav1.3 and Cav1.4 from porcine retinas, and it increased the LTCC currents and facilitated voltage-dependent activation in HEK cells co-transfected with RS1 and Cav1.3 or Cav1.4, thus providing evidence of a functional interaction between RS1 and LTCCs. The interaction between RS1 and Cav1.3 did not change the calcium-dependent inactivation of Cav1.3. In mice lacking RS1, the expression of Cav1.3 and Cav1.4 in the retina decreased, while in mice with Cav1.4 deletion, the retinal level of RS1 decreased. These results provide important evidence that RS1 is not only an adhesive protein promoting cell-cell adhesion, it is essential for anchoring other membrane proteins including ion channels and enhancing their function in the retina.
2016-06-08 | Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client
Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory Pγ-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and Pγ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants. Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory Pγ-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and Pγ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants.
other
2024-08-07 | Anti-TRPM1 autoantibody-positive unilateral melanoma associated retinopathy (MAR) triggered by immunotherapy recapitulates functional and structural details of TRPM1-associated congenital stationary night blindness.
To describe the retinal phenotype of an unusual case of anti-TRPM1 autoantibody-positive unilateral melanoma-associated retinopathy (MAR) triggered by nivolumab therapy and compare with the phenotype of TRPM1-associated Congenital Stationary Night Blindness (TRPM1-CSNB). Unilateral MAR was diagnosed 3 months after starting nivolumab therapy for consolidation of a successfully treated melanoma. Retinal autoantibodies against TRPM1 were identified. ffERG, microperimetry and static chromatic perimetry confirmed unilateral ON-Bipolar Cell (ON-BPC) dysfunction and central rod sensitivity losses in the left eye; the contralateral eye was normal. There was borderline ganglion cell (GCL) and inner nuclear layer (INL) thinning, but a significantly thinner inner plexiform layer (IPL) in the affected compared to the unaffected eye. Longitudinal reflectivity profiles (LRPs) demonstrated an abnormal inner plexiform layer (IPL) lamination in the involved eye. Nearly identical changes were documented in two cases of TRMP1-cCSNB and in a case of anti-TRPM1 autoantibody-negative MAR. The functional changes partially recovered with discontinuation of the medication without added immunosuppression. Comparisons between the affected and unaffected eye in this unilateral MAR case revealed inner retinal abnormalities and abnormal lamination of the IPL associated with the classical retina-wide ON-BPC dysfunction, and localized central rod-mediated sensitivity losses. A nearly identical structural phenotype in two cases of cCSNB and a case of anti-TRPM1 autoantibody-negative MAR supports a specific structural-functional phenotype for these conditions with ON-BPC dysfunction.
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