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Colour vision is widespread in marine vertebrates but is notably lacking in whales, dolphins, seals, and apparently also sharks. All sharks studied to date possess only a single spectral class of cone and are thus potentially totally colour blind. The reason why sharks lack colour vision is unclear, but as the visual pigments of only a handful of this large and ecologically diverse taxon have been studied, more data are required to address this question. Here, we assembled the retinal transcriptomes of nine species from seven families and three orders within the superorder Galeomorphii to screen for visual opsin and phototransduction genes. We reveal that cone monochromacy is widespread in galeomorph sharks, but the type of cone opsin expressed varies, with lamniform and orectolobiform sharks expressing an LWS opsin, and carcharhiniform and heterodontiform sharks expressing an RH2 opsin. Cone monochromacy has evolved from a dichromatic ancestral state at least four times, implying strong selection pressure to prioritise achromatic over chromatic vision. While all species express the GRK1A and GRK7 isoforms of G protein-coupled receptor kinase, only sharks with the LWS cone opsin express the GRK1B isoform, which suggests that non-spectral functions of photoreception may have influenced, or result from, the opsin complement in the shark retina. Finally, we show that the shark RH1 opsin gene shows evidence of positive selection at sites known to influence pigment kinetics (i.e. metarhodopsin II stability) and that the rate of retinal release likely differs substantially between species in ways that reflect their physiology and ecology., (© The Author(s) 2025. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.) more...

Blue cone monochromacy (BCM) is an X-linked retinal disorder caused by mutations in the OPN1LW/OPN1MW gene locus, resulting in impaired cone function and structural degeneration. We conducted a comparative analysis of AAV-mediated gene therapy in Opn1lw/Opn1mw double knockout (DKO) and Opn1mw C198R /Opn1sw -/- (C198R) BCM mouse models and evaluated the therapeutic window, efficacy, and longevity. Our results demonstrate that the AAV8-Y733F capsid achieved superior cone rescue compared to AAV5. While both DKO and C198R models showed similar therapeutic windows and rescue longevity, treatment efficacy decreased markedly in older mutant mice. Structural analysis revealed that aged cones in both models displayed degenerative changes, including mislocalized mitochondria and compromised connecting cilia. At the molecular level, we observed reduced AAV-mediated transgene expression in DKO and C198R older cones, which may result from decreased transduction efficiency, decreased circular episome stability, genome-wide transcription/translation downregulation, targeted mRNA/protein degradation, or overall cone degeneration. Notably, the cone-specific promoters for Pde6c and Cngb3 maintained robust activity in degenerating cones. These findings suggest that combining an efficient AAV serotype with an optimized cone promoter could be a viable approach to extend the therapeutic window and enhance treatment longevity for BCM patients. more...

High-level visual functions such as reading and face recognition rely on global processes, which are often insensitive to high spatial frequencies. However, it is unknown whether a sharp cone signal is necessary for the development of these skills or whether a blurry rod signal is sufficient. CNGA3/B3-achromatopsia is a congenital disease stemming from cone dysfunction, leading to rod-only vision characterized by nystagmus, impaired acuity, and complete color blindness. We tested reading and face recognition in CNGA3/B3-achromatopsia patients (ACHM) to determine whether a rod signal is sufficient for these skills to develop. We tested 10 ACHM and 10 controls in three experiments under dark and light conditions. Initially, we evaluated acuity along the eccentricity axis. Later, we tested reading speed and upright/inverted face matching accuracy while tracking participants’ eye movements. Given that ACHM patients’ acuity under light conditions resembled that of controls under dark conditions, we selected these conditions for comparison. Remarkably, ACHM reading speed, face recognition abilities, and susceptibility to face inversion were not inferior to those of controls. Additionally, ACHM patients exhibited similar eye movements to controls, focusing their attention on specific areas of words and faces that indicate expertise. Despite the evident low-level limitations, ACHM patients demonstrated notable high-level visual skills, suggesting that rod-only vision is sufficient for the development of proficient reading and face recognition. These findings not only corroborate empirical evidence for high-level vision models but also enrich the discussion regarding the reasons for high-level deficits observed in individuals who have gained sight late in life. more...

L-cone opsin expression by gene therapy is a promising treatment for blue cone monochromacy (BCM) caused by congenital lack of long- and middle-wavelength-sensitive (L/M) cone function. Eight patients with BCM and confirmed pathogenic variants at the OPN1LW/OPN1MW gene cluster participated. Optical coherence tomography (OCT), chromatic perimetry, chromatic microperimetry, chromatic visual acuity (VA), and chromaticity thresholds were performed with unmodified commercial equipment and/or methods available in the public domain. Adaptive optics scanning laser ophthalmoscope (AOSLO) imaging was performed in a subset of patients. Outer retinal changes were detectable by OCT with an age-related effect on the foveal disease stage. Rod and short-wavelength-sensitive (S) cone functions were relatively retained by perimetry, although likely impacted by age-related increases in the pre-retinal absorption of short-wavelength lights. The central macula showed a large loss of red sensitivity on dark-adapted microperimetry. Chromatic VAs with high-contrast red gratings on a blue background were not detectable. Color vision was severely deficient. AOSLO imaging showed reduced total cone density with majority of the population being non-waveguiding. This study developed and evaluated specialized outcomes that will be needed for the determination of efficacy and safety in human clinical trials. Dark-adapted microperimetry with a red stimulus sampling the central macula would be a key endpoint to evaluate the light sensitivity improvements. VA changes specific to L-opsin can be measured with red gratings on a bright blue background and should also be considered as outcome measures in future interventional trials. more...

The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases. more...

Abstract Background Blue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM. Case presentation We report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather. Conclusions The present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history. more...

Blue cone monochromacy (BCM) is a congenital vision disorder affecting both middle-wavelength (M) and long-wavelength (L) cone photoreceptors of the human retina. BCM results from abolished expression of green and red light-sensitive visual pigments expressed in M- and L-cones, respectively. Previously, we showed that gene augmentation therapy to deliver either human L- or M-opsin rescues dorsal M-opsin dominant cone photoreceptors structurally and functionally in treated M-opsin knockout (Opn1mw−/−) mice. Although Opn1mw−/− mice represent a disease model for BCM patients with deletion mutations, at the cellular level, dorsal cones of Opn1mw−/− mice still express low levels of S-opsin, which are different from L- and M-cones of BCM patients carrying a congenital opsin deletion. To determine whether BCM cones lacking complete opsin expression from birth would benefit from AAV-mediated gene therapy, we evaluated the outcome of gene therapy, and determined the therapeutic window and longevity of rescue in a mouse model lacking both M- and S-opsin (Opn1mw−/−/Opn1sw−/−). Our data show that cones of Opn1mw−/−/Opn1sw−/− mice are viable at younger ages but undergo rapid degeneration. AAV-mediated expression of human L-opsin promoted cone outer segment regeneration and rescued cone-mediated function when mice were injected subretinally at 2 months of age or younger. Cone-mediated function and visually guided behavior were maintained for at least 8 months post-treatment. However, when mice were treated at 5 and 7 months of age, the chance and effectiveness of rescue was significantly reduced, although cones were still present in the retina. Crossing Opn1mw−/−/Opn1sw−/− mice with proteasomal activity reporter mice (UbG76V–GFP) did not reveal GFP accumulation in Opn1mw−/−/Opn1sw−/− cones eliminating impaired degradation of ubiquitinated proteins as stress factor contributing to cone loss. Our results demonstrate that AAV-mediated gene augmentation therapy can rescue cone structure and function in a mouse model with a congenital opsin deletion, but also emphasize the importance that early intervention is crucial for successful therapy. [ABSTRACT FROM AUTHOR] more...

Novel therapeutic approaches for treating inherited retinal degenerations (IRDs) prompt a need to understand which patients with impaired vision have the anatomical potential to gain from participation in a clinical trial. We used supervised machine learning to predict foveal function from foveal structure in blue cone monochromacy (BCM), an X-linked congenital cone photoreceptor dysfunction secondary to mutations in the OPN1LW/OPN1MW gene cluster. BCM patients with either disease-associated large deletion or missense mutations were studied and results compared with those from subjects with other forms of IRD and various degrees of preserved central structure and function. A machine learning technique was used to associate foveal sensitivities and best-corrected visual acuities to foveal structure in IRD patients. Two random forest (RF) models trained on IRD data were applied to predict foveal function in BCM. A curve fitting method was also used and results compared with those of the RF models. The BCM and IRD patients had a comparable range of foveal structure. IRD patients had peak sensitivity at the fovea. Machine learning could successfully predict foveal sensitivity (FS) results from segmented or un-segmented optical coherence tomography (OCT) input. Application of machine learning predictions to BCM at the fovea showed differences between predicted and measured sensitivities, thereby defining treatment potential. The curve fitting method provided similar results. Given a measure of visual acuity (VA) and foveal outer nuclear layer thickness, the question of how many lines of acuity would represent the best efficacious result for each BCM patient could be answered. We propose that foveal vision improvement potential in BCM is predictable from retinal structure using machine learning and curve fitting approaches. This should allow estimates of maximal efficacy in patients being considered for clinical trials and also guide decisions about dosing. more...

Abstract Blue cone monochromacy (BCM) is characterized by loss of function of both OPN1LW (the first) and OPN1MW (the downstream) genes on the X chromosome. The purpose of this study was to investigate the first and downstream genes in the OPN1LW/OPN1MW array in four unrelated Japanese males with BCM. In Case 1, only one gene was present. Abnormalities were found in the promoter, which had a mixed unique profile of first and downstream gene promoters and a −71A > C substitution. As the promoter was active in the reporter assay, the cause of BCM remains unclear. In Case 2, the same novel mutation, M273K, was present in exon 5 of both genes in a two-gene array. The mutant pigments showed no absorbance at any of the wavelengths tested, suggesting that the mutation causes pigment dysfunction. Case 3 had a large deletion including the locus control region and entire first gene. Case 4 also had a large deletion involving exons 2–6 of the first gene. As an intact LCR was present upstream and one apparently normal downstream gene was present, BCM in Case 4 was not ascribed solely to the deletion. The deletions in Cases 3 and 4 were considered to have been caused by non-homologous recombination. more...

Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials., Methods: Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests., Results: All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities., Conclusions: Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM., Translational Relevance: Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease. more...

Abstract Cones are responsible for daylight, central, high acuity and color vision. Three proteins found in human cones, i.e. long-wavelength (L)-, middle-wavelength (M)-, and short-wavelength sensitive (S)-opsins, are responsible for red, green and blue color recognition, respectively. Human blue cone monochromacy (BCM) is characterized by functional loss of both L- and M-cone opsins due to mutations in the OPN1LW/OPN1MW gene cluster on the X chromosome. BCM patients, who rely on their vision from only S-cones and rods, suffer severely reduced visual acuity and impaired color vision. Recent studies show that there is sufficient cone structure remaining in the central fovea of BCM patients to consider AAV-mediated gene augmentation therapy. In contrast, mouse retina has only two opsins, S-opsin and M-opsin, but no L-opsin. We generated an M-opsin knockout mouse (Opn1mw −/−) expressing only S-opsin as a model for human BCM. We show that recombinant M-opsin delivered by AAV5 vectors rescues M-cone function in Opn1mw −/− mice. We also show that AAV delivered M-opsin localizes in the dorsal cone outer segments, and co-localizes with S-opsin in the ventral retina. Our study demonstrates that cones without M-opsin remain viable and respond to gene augmentation therapy, thereby providing proof-of-concept for cone function restoration in BCM patients. more...

Purpose: Blue cone monochromacy (BCM) is a rare inherited cone disorder in which both long- (L-) and middle- (M-) wavelength sensitive cone classes are either impaired or nonfunctional. Assessing genotype-phenotype relationships in BCM can improve our understanding of retinal development in the absence of functional L- and M-cones. Here we examined foveal cone structure in patients with genetically-confirmed BCM, using adaptive optics scanning light ophthalmoscopy (AOSLO)., Methods: Twenty-three male patients (aged 6-75 years) with genetically-confirmed BCM were recruited for high-resolution imaging. Eight patients had a deletion of the locus control region (LCR), and 15 had a missense mutation-Cys203Arg-affecting the first two genes in the opsin gene array. Foveal cone structure was assessed using confocal and non-confocal split-detection AOSLO across a 300 × 300 µm area, centered on the location of peak cell density., Results: Only one of eight patients with LCR deletions and 10 of 15 patients with Cys203Arg mutations had analyzable images. Mean total cone density for Cys203Arg patients was 16,664 ± 11,513 cones/mm2 (n = 10), which is, on average, around 40% of normal. Waveguiding cone density was 2073 ± 963 cones/mm2 (n = 9), which was consistent with published histological estimates of S-cone density in the normal eye. The one patient with an LCR deletion had a total cone density of 10,246 cones/mm2 and waveguiding density of 1535 cones/mm2., Conclusions: Our results show that BCM patients with LCR deletions and Cys203Arg mutations have a population of non-waveguiding photoreceptors, although the spectral identity and level of function remain unknown. more...

High-level visual functions such as reading and face recognition rely on global processes, which are often insensitive to high spatial frequencies. However, it is unknown whether a sharp cone signal is necessary for the development of these skills or whether a blurry rod signal is sufficient. CNGA3/B3-achromatopsia is a congenital disease stemming from cone dysfunction, leading to rod-only vision characterized by nystagmus, impaired acuity, and complete color blindness. We tested reading and face recognition in CNGA3/B3-achromatopsia patients (ACHM) to determine whether a rod signal is sufficient for these skills to develop. We tested 10 ACHM and 10 controls in three experiments under dark and light conditions. Initially, we evaluated acuity along the eccentricity axis. Later, we tested reading speed and upright/inverted face matching accuracy while tracking participants' eye movements. Given that ACHM patients' acuity under light conditions resembled that of controls under dark conditions, we selected these conditions for comparison. Remarkably, ACHM reading speed, face recognition abilities, and susceptibility to face inversion were not inferior to those of controls. Additionally, ACHM patients exhibited similar eye movements to controls, focusing their attention on specific areas of words and faces that indicate expertise. Despite the evident low-level limitations, ACHM patients demonstrated notable high-level visual skills, suggesting that rod-only vision is sufficient for the development of proficient reading and face recognition. These findings not only corroborate empirical evidence for high-level vision models but also enrich the discussion regarding the reasons for high-level deficits observed in individuals who have gained sight late in life. [ABSTRACT FROM AUTHOR] more...

Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy caused by mutations in the red and green cone opsin genes. The aim of this study was to establish the clinical, genetic, and electrophysiological characteristics of a specific form of BCM., Methods: Patients harboring mutations in the OPN1LW/OPN1MW genes underwent a full clinical examination, including ocular examination, color vision, full-field electroretinography, color fundus and autofluorescence photography, and optical coherence tomography. Genetic analysis was performed using whole-exome sequencing, duplex PCR, PCR/restriction fragment length polymorphism, and Sanger sequencing. IBM SPSS Statistics v. 21.0 was used for the data analysis., Results: Twenty-five patients harboring various haplotypes in exon 3 of the OPN1LW/OPN1MW genes were recruited. They showed a milder incomplete phenotype of BCM than the typical BCM control group. They presented significantly better visual acuity (logarithm of the minimum angle of resolution [logMAR] 0.48 ± 0.26 vs. 1.10 ± 0.54; p < 0.0001) and a highly myopic refraction (-7.81 ± 5.81 D vs. -4.78 ± 5.27 D; p = 0.0222) compared with the BCM control group. The study group had higher 30-Hz cone flicker responses (28.60 ± 15.02 µv; n = 24), whereas the BCM group had none (0.66 ± 2.12 µv; n = 21; p < 0.0001). The Lanthony 15-HUE desaturated test was variable for the exon 3 haplotype group, with a tendency toward the deutan-protan axis., Conclusions: The present study included genetic and clinical data from the largest cohort of patients with exon 3 haplotypes that were previously shown to cause missplicing of the OPN1LW and OPN1MW genes. Analysis of the clinical data revealed better best-corrected visual acuity, more severe myopia, and higher 30-Hz cone flicker responses in the patients with exon 3 haplotypes than in those with typical BCM., (Copyright © 2022 Molecular Vision.) more...

Background: To clarify the diagnosis of a Chinese patient with novel double heterozygous in the NR2E3 and OPN1LW genes and describe the clinical features. Materials and Methods: A 47-year-old man presented with an 8-year history of decreased vision and poor night vision. Based on his clinical phenotype, we focused on 36 genes associated with these characteristics. Possible pathogenic mutation sites were screened by next-generation sequencing (NGS), which showed novel mutations in the NR2E3 and OPN1LW genes. These mutations were confirmed in the patient's sister and daughter by Sanger sequencing. To clarify the diagnosis, the clinical symptoms of the patient were observed and analyzed in combination with comprehensive ophthalmologic examinations. Results: Genetic analysis identified the presence of novel double heterozygous of c.361G>A; p.E121K in NR2E3, a gene responsible for enhanced S-cone syndrome (ESCS; OMIM #268100) and c.244A>G; p.K82E in OPN1LW, a gene responsible for blue cone monochromacy (BCM; OMIM#303700). No typical clinical presentation or fundus features were found. The differential diagnosis of ESCS was excluded by electroretinography (ERG) due to the lack of characteristic abnormalities associated with ESCS. Based on the clinical manifestations and comprehensive ophthalmologic examinations, the patient was diagnosed with BCM. Conclusions: The novel mutations of c.244A>G; p.K82E in the OPN1LW gene and c.361G>A; p.E121K in the NR2E3 gene both cause BCM, but OPN1LW gene mutation dominated the retinal degeneration, resulting in the clinical features observed in this patient. These novel double heterozygous may be helpful for future genetic diagnosis and treatment for BCM. [ABSTRACT FROM AUTHOR] more...