RESUMEN
PURPOSE: CNGA3 encoding the main subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors is one of the major disease-associated genes for achromatopsia. Most CNGA3 variants are missense variants with the majority being functionally uncharacterized and therefore hampering genetic diagnosis. In light of potential gene therapy, objective variant pathogenicity assessment is essential. METHODS: We established a medium-throughput aequorin-based luminescence bioassay allowing mutant CNGA3 channel function assessment via quantification of CNGA3 channel-mediated calcium influx in a cell culture system, thereby enabling American College of Medical Genetics and Genomics/Association for Molecular Pathology-based variant re-classification. RESULTS: We provide functional read-out obtained for 150 yet uncharacterized CNGA3 missense substitutions of which 55 were previously categorized as variants of uncertain significance (VUS) identifying 25 as functionally normal and 125 as functionally abnormal. These data enabled the American College of Medical Genetics and Genomics/ Association for Molecular Pathology-based variant re-classification of 52/55 VUS as either benign, likely benign, or likely pathogenic reaching a VUS re-classification rate of 94.5%. CONCLUSION: Our aequorin-based bioassay allows functionally ensured clinical variant interpretation for 150 CNGA3 missense variants enabling and supporting VUS re-classification and assuring molecular diagnosis to patients affected by CNGA3-associated achromatopsia, hereby identifying patients eligible for future gene therapy trials on this disease.
Asunto(s)
Defectos de la Visión Cromática , Humanos , Defectos de la Visión Cromática/diagnóstico , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Aequorina/genética , Células Fotorreceptoras Retinianas Conos/patología , Mutación Missense/genética , Genómica , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genéticaRESUMEN
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.
Asunto(s)
Defectos de la Visión Cromática , Masculino , Humanos , Defectos de la Visión Cromática/diagnóstico , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Fóvea Central/patología , Células Fotorreceptoras Retinianas Conos/patología , Oftalmoscopía/métodosRESUMEN
Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.
Asunto(s)
Defectos de la Visión Cromática , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/metabolismo , Defectos de la Visión Cromática/patología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/química , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Humanos , Fototransducción , Mutación Missense , Células Fotorreceptoras Retinianas ConosRESUMEN
Achromatopsia (ACHM) is an inherited autosomal recessive disease lacking cone photoreceptors functions. In this study, we characterize the time-frequency representation of the full-field electroretinogram (ffERG) component oscillatory potentials (OPs), to investigate the connections between photoreceptors and the inner retinal network using ACHM as a model. Time-frequency characterization of OPs was extracted from 52 controls and 41 achromat individuals. The stimulation via ffERG was delivered under dark-adaptation (DA, 3.0 and 10.0 cd·s·m-2) to assess mixed rod-cone responses. The ffERG signal was subsequently analyzed using a continuous complex Morlet transform. Time-frequency maps of both DA conditions show the characterization of OPs, disclosing in both groups two distinct time-frequency windows (~70-100 Hz and >100 Hz) within 50 ms. Our main result indicates a significant cluster (p < 0.05) in both conditions of reduced relative power (dB) in ACHM people compared to controls, mainly at the time-frequency window >100 Hz. These results suggest that the strongly reduced but not absent activity of OPs above 100 Hz is mostly driven by cones and only in small part by rods. Thus, the lack of cone modulation of OPs gives important insights into interactions between photoreceptors and the inner retinal network and can be used as a biomarker for monitoring cone connection to the inner retina.
Asunto(s)
Potenciales de Acción , Defectos de la Visión Cromática/patología , Electrorretinografía/métodos , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Bastones/patología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Estimulación LuminosaRESUMEN
Sporadic occurrence of inherited eye disorders has been reported in cattle but so far pathogenic variants were found only for rare forms of cataract but not for retinopathies. The aim of this study was to characterize the phenotype and the genetic aetiology of a recessive form of congenital day-blindness observed in several cases of purebred Original Braunvieh cattle. Electroretinography in an affected calf revealed absent cone-mediated function, whereas the rods continue to function normally. Brain areas involved in vision were morphologically normal. When targeting cones by immunofluorescence, a decrease in cone number and an accumulation of beta subunits of cone cyclic-nucleotide gated channel (CNGB3) in the outer plexiform layer of affected animals was obvious. Achromatopsia is a monogenic Mendelian disease characterized by the loss of cone photoreceptor function resulting in day-blindness, total color-blindness, and decreased central visual acuity. After SNP genotyping and subsequent homozygosity mapping with twelve affected cattle, we performed whole-genome sequencing and variant calling of three cases. We identified a single missense variant in the bovine CNGB3 gene situated in a ~2.5 Mb homozygous genome region on chromosome 14 shared between all cases. All affected cattle were homozygous carriers of the p.Asp251Asn mutation that was predicted to be deleterious, affecting an evolutionary conserved residue. In conclusion, we have evidence for the occurrence of a breed-specific novel CNGB3-related form of recessively inherited achromatopsia in Original Braunvieh cattle which we have designated OH1 showing an allele frequency of the deleterious allele of ~8%. The identification of carriers will enable selection against this inherited disorder. The studied cattle might serve as an animal model to further elucidate the function of CNGB3 in mammals.
Asunto(s)
Alelos , Defectos de la Visión Cromática/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Mutación Missense , Subunidades de Proteína/genética , Células Fotorreceptoras Retinianas Conos/metabolismo , Sustitución de Aminoácidos , Animales , Asparagina/metabolismo , Ácido Aspártico/metabolismo , Bovinos , Defectos de la Visión Cromática/diagnóstico por imagen , Defectos de la Visión Cromática/metabolismo , Defectos de la Visión Cromática/patología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/deficiencia , Electrorretinografía , Femenino , Expresión Génica , Frecuencia de los Genes , Homocigoto , Masculino , Fenotipo , Subunidades de Proteína/deficiencia , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Bastones/citología , Células Fotorreceptoras Retinianas Bastones/metabolismo , Secuenciación Completa del GenomaRESUMEN
Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1-71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I-IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.
Asunto(s)
Defectos de la Visión Cromática/patología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Mutación , Enfermedades de la Retina/patología , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Estudios de Cohortes , Defectos de la Visión Cromática/genética , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades de la Retina/genética , Eslovenia , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects.
Asunto(s)
Defectos de la Visión Cromática/genética , Proteínas del Ojo/genética , Fóvea Central/anomalías , Glicoproteínas de Membrana/genética , Opsinas de Bastones/genética , Adulto , Defectos de la Visión Cromática/patología , Humanos , Masculino , Mutación , LinajeRESUMEN
Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.
Asunto(s)
Cromosomas Humanos Par 2/genética , Defectos de la Visión Cromática/patología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Padre , Mutación , Disomía Uniparental , Adolescente , Defectos de la Visión Cromática/genética , Femenino , Genes Recesivos , Humanos , Masculino , Linaje , FenotipoRESUMEN
Many citizen science projects depend on colour vision. Examples include classification of soil or water types and biological monitoring. However, up to 1 in 11 participants are colour blind. We simulate the impact of various forms of colour blindness on measurements with the Forel-Ule scale, which is used to measure water colour by eye with a 21-colour scale. Colour blindness decreases the median discriminability between Forel-Ule colours by up to 33% and makes several colour pairs essentially indistinguishable. This reduces the precision and accuracy of citizen science data and the motivation of participants. These issues can be addressed by including uncertainty estimates in data entry forms and discussing colour blindness in training materials. These conclusions and recommendations apply to colour-based citizen science in general, including other classification and monitoring activities. Being inclusive of the colour blind increases both the social and scientific impact of citizen science.
Asunto(s)
Ciencia Ciudadana/métodos , Defectos de la Visión Cromática/patología , Simulación por Computador , Humanos , MotivaciónRESUMEN
Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (-0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.
Asunto(s)
Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Mutación , Adolescente , Adulto , Biomarcadores , Preescolar , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Análisis Mutacional de ADN , Proteínas del Ojo/genética , Femenino , Proteínas de Unión al GTP Heterotriméricas/genética , Humanos , Estudios Longitudinales , Masculino , Linaje , Fenotipo , Pronóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
Purpose: Psychophysical and genetic testing provide substantial information about color vision phenotype and genotype. However, neither reveals how color vision phenotypes and genotypes manifest themselves in individual cones, where color vision and its anomalies are thought to originate. Here, we use adaptive-optics phase-sensitive optical coherence tomography (AO-PSOCT) to investigate these relationships. Methods: We used AO-PSOCT to measure cone function-optical response to light stimulation-in each of 16 human subjects with different phenotypes and genotypes of color vision (five color-normal, three deuteranopic, two protanopic, and six deuteranomalous trichromatic subjects). We classified three spectral types of cones (S, M, and L), and we measured cone structure-namely cone density, cone mosaic arrangement, and spatial arrangement of cone types. Results: For the different phenotypes, our cone function results show that (1) color normals possess S, M, and L cones; (2) deuteranopes are missing M cones but are normal otherwise; (3) protanopes are missing L cones but are normal otherwise; and (4) deuteranomalous trichromats are missing M cones but contain evidence of at least two subtypes of L cones. Cone function was consistent with the subjects' genotype in which only the first two M and L genes in the gene array are expressed and was correlated with the estimated spectral separation between photopigments, including in the deuteranomalous trichromats. The L/M cone ratio was highly variable in the color normals. No association was found between cone density and the genotypes and phenotypes investigated, and the cone mosaic arrangement was altered in the dichromats. Conclusions: AO-PSOCT is a novel method for assessing color vision phenotype and genotype in single cone cells.
Asunto(s)
Defectos de la Visión Cromática/genética , Visión de Colores/genética , Células Fotorreceptoras Retinianas Conos/metabolismo , Pigmentos Retinianos/metabolismo , Adulto , Percepción de Color/fisiología , Defectos de la Visión Cromática/metabolismo , Defectos de la Visión Cromática/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Células Fotorreceptoras Retinianas Conos/patología , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.
Asunto(s)
Defectos de la Visión Cromática/etiología , Defectos de la Visión Cromática/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo II/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/deficiencia , Células Fotorreceptoras Retinianas Conos/metabolismo , Animales , Biomarcadores , Defectos de la Visión Cromática/patología , GMP Cíclico/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo II/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Estrés del Retículo Endoplásmico , Técnica del Anticuerpo Fluorescente , Expresión Génica , Ratones , Ratones Noqueados , Microscopía Confocal , Modelos Biológicos , Degeneración Retiniana/etiología , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Respuesta de Proteína DesplegadaRESUMEN
Purpose: Achromatopsia is a congenital autosomal recessive cone disorder, and it has been found to be associated with six genes. However, pathogenic variants in these six genes have been identified in patients with various retinal dystrophies with the exception of achromatopsia. Thus, this study aims to investigate the contribution of these genes in hereditary retinal diseases and the potential genotype-phenotype correlations. Methods: Biallelic variants in six achromatopsia-related genes, namely, CNGA3, CNGB3, GNAT2, ATF6, PDE6C, and PDE6H, were analyzed based on data obtained from 7,195 probands with different eye conditions. A systematic genotype-phenotype analysis of these genes was performed based on these data, along with the data reported in the literature. Results: Biallelic potential pathogenic variants (PPVs) in five of the six genes were identified in 119 probands with genetic eye diseases. The variants in CNGA3 were the most common and accounted for 81.5% (97/119). Of the 119 probands, 62.2% (74/119) have cone-rod dystrophy, whereas only 25.2% (30/119) have achromatopsia. No biallelic pathogenic variants in these genes were identified in patients with rod-dominant degeneration. A systematic review of genotypes and phenotypes revealed certain characteristics of each of the six genes, providing clues for the pathogenicity evaluation of the variants of the genes. Conclusions: PPVs in the six genes were identified in various inherited retinal degeneration diseases, most of which are cone-dominant diseases but no rod-dominant diseases based on the data from a cohort of 7,195 probands with different eye conditions. The systematic genotype-phenotype analysis of these genes will be useful in drafting guidelines for the clinical genetic diagnostic application for the investigated genes.
Asunto(s)
Defectos de la Visión Cromática/genética , Distrofias de Conos y Bastones/genética , 3',5'-GMP Cíclico Fosfodiesterasas/genética , Factor de Transcripción Activador 6/genética , Alelos , Estudios de Cohortes , Defectos de la Visión Cromática/congénito , Defectos de la Visión Cromática/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/química , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Análisis Mutacional de ADN , Electrorretinografía , Proteínas del Ojo/genética , Familia , Estudios de Asociación Genética , Genotipo , Proteínas de Unión al GTP Heterotriméricas/genética , Humanos , Mutación , Fenotipo , Células Fotorreceptoras Retinianas Conos/patología , Secuenciación del ExomaRESUMEN
Purpose: To examine the foveal avascular zone (FAZ) in patients with congenital achromatopsia (ACHM). Methods: Forty-two patients with genetically confirmed ACHM were imaged either with Optovue's AngioVue system or Zeiss's Plex Elite 9000, and the presence or absence of a FAZ was determined. For images where a FAZ was present and could be confidently segmented, FAZ area, circularity index, and roundness were measured and compared with previously published normative values. Structural optical coherence tomography images were acquired to assess the degree of foveal hypoplasia (number and thickness of inner retinal layers present at the fovea). Results: A FAZ was present in 31 of 42 patients imaged (74%), although no determination could be made for 11 patients due to poor image quality (26%). The mean ± SD FAZ area for the ACHM retina was 0.281 ± 0.112 mm2, which was not significantly different from the previously published normative values (P = 0.94). However, their FAZs had decreased circularity (P < 0.0001) and decreased roundness (P < 0.0001) compared to the normative cohort. In the patients with ACHM examined here, the FAZ area decreased as the number and thickness of the retained inner retinal layers increased. Conclusions: Our data demonstrate that despite the presence of foveal hypoplasia, patients with ACHM can have a FAZ. This is distinct from other conditions associated with foveal hypoplasia, which generally show an absence of the FAZ. In ACHM, FAZ formation does not appear to be sufficient for complete pit formation, contrary to some models of foveal development.
Asunto(s)
Defectos de la Visión Cromática/congénito , Fóvea Central/patología , Adolescente , Adulto , Anciano , Niño , Defectos de la Visión Cromática/diagnóstico por imagen , Defectos de la Visión Cromática/patología , Femenino , Fóvea Central/irrigación sanguínea , Fóvea Central/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Retina/diagnóstico por imagen , Retina/patología , Vasos Retinianos/diagnóstico por imagen , Vasos Retinianos/patología , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
Background: Achromatopsia (ACHM) is an inherited retinal disease affecting the cone cell function. To date, six pathogenic genes of ACHM have been identified. However, the diagnostic and therapeutic methods of this disorder remain limited. Herein, to characterize the clinical features and genetic causes of three affected siblings in a Chinese family with ACHM, we used target next-generation sequencing (NGS) and found new pathogenic factors associated with ACHM in this family. Materials and methods: Three patients with ACHM and three healthy family members were included in this study. All participants received comprehensive ophthalmic tests. NGS approach was performed on the patients to determine the causative mutation for this family. The silico analysis was also applied to predict the pathogenesis of identified mutations. Results: Genetic assessments revealed compound heterozygous mutations of the PDE6C gene (c.1413 + 1 G > C, c.305 G > A), carried by all three patients. Both mutations were novel and predicted to be deleterious by six types of online predictive software. The heterozygous PDE6C missense mutation (c.305 G > A) was found from the mother and the heterozygous PDE6C splice site mutation (c.1413 + 1 G > C) was found in the father and all the children. All patients in the family showed typical signs and symptoms of ACHM. Conclusions: We report novel compound heterozygous PDE6C mutations in causing ACHM and further confirm the clinical diagnosis. Our study extends the genotypic spectrums for PDE6C-ACHM and better illustrates its genotype-phenotype correlations, which would help the ACHM patients with better genetic diagnosis, prognosis, and gene treatment.
Asunto(s)
Pueblo Asiatico/genética , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Proteínas del Ojo/genética , Estudios de Asociación Genética , Mutación , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , LinajeRESUMEN
This paper analyzes, through computational simulations, which spectral filters increase the number of discernible colors (NODC) of subjects with normal color vision, as well as red-green anomalous trichromats and dichromats. The filters are selected from a set of filters in which we have modeled spectral transmittances. With the selected filters we have carried out simulations performed using the spectral reflectances captured either by a hyperspectral camera or by a spectrometer. We have also studied the effects of these filters on color coordinates. Finally, we have simulated the results of two widely used color blindness tests: Ishihara and Farnsworth-Munsell 100 Hue (FM100). In these analyses the selected filters are compared with the commercial filters from EnChroma and VINO companies. The results show that the increase in NODC with the selected filters is not relevant. The simulation results show that none of these chosen filters help color vision deficiency (CVD) subjects to pass the set of color blindness tests studied. These results obtained using standard colorimetry support the hypothesis that the use of color filters does not cause CVDs to have a perception similar to that of a normal observer.
Asunto(s)
Percepción de Color/fisiología , Defectos de la Visión Cromática/rehabilitación , Óptica y Fotónica/métodos , Defectos de la Visión Cromática/patología , Filtración , Humanos , Dispositivos Ópticos , Óptica y Fotónica/instrumentaciónRESUMEN
Purpose: The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. Methods: Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. Results: All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. Conclusions: The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.
Asunto(s)
Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Subunidades gamma de la Proteína de Unión al GTP/genética , Células Fotorreceptoras Retinianas Conos/patología , Adolescente , Adulto , Niño , Pruebas de Percepción de Colores , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Nistagmo Patológico/diagnóstico , Oftalmoscopía , Imagen Óptica , Linaje , Fenotipo , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Purpose: To determine the interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Methods: Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8-44 years, 14 females) with genetically confirmed CNGA3- or CNGB3-associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 µm sampling window within the rod-free zone. The mean and standard deviation (SD) of inter-cell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. Results: PCD (mean ± SD) was 17,530 ± 9,614 cones/mm2 and 17,638 ± 9,753 cones/mm2 for right and left eyes, respectively (p = .677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 µm and 9.24 ± 2.55 µm for right and left eyes, respectively (p = .410, paired t-test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 µm and 0.16 ± 0.04 µm for right and left eyes, respectively (p = .562, paired t-test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. Conclusions: These results demonstrate the interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.
Asunto(s)
Defectos de la Visión Cromática/congénito , Defectos de la Visión Cromática/patología , Fóvea Central/patología , Células Fotorreceptoras Retinianas Conos/patología , Adolescente , Adulto , Recuento de Células , Niño , Defectos de la Visión Cromática/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Análisis Mutacional de ADN , Femenino , Fóvea Central/diagnóstico por imagen , Humanos , Masculino , Oftalmoscopía , Topografía Médica , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Color provides valuable information about the environment, yet the exact mechanisms explaining how colors appear to us remain poorly understood. Retinal signals are processed in the visual cortex through high-level mechanisms that link color perception with top-down expectations and knowledge. Here, we review the neuroimaging evidence about color processing in the brain, and how it is affected by acquired brain lesions in humans. Evidence from patients with brain-damage suggests that high-level color processing may be divided into at least three modules: perceptual color experience, color naming, and color knowledge. These modules appear to be functionally independent but richly interconnected, and serve as cortical relays linking sensory and semantic information, with the final goal of directing object-related behavior. We argue that the relations between colors and their objects are key mechanisms to understand high-level color processing.
Asunto(s)
Agnosia/fisiopatología , Anomia/fisiopatología , Corteza Cerebral/fisiopatología , Percepción de Color/fisiología , Defectos de la Visión Cromática/fisiopatología , Vías Visuales/fisiopatología , Agnosia/patología , Anomia/patología , Corteza Cerebral/patología , Defectos de la Visión Cromática/patología , Humanos , Vías Visuales/patologíaRESUMEN
Purpose: Mutations in six genes have been associated with achromatopsia (ACHM): CNGA3, CNGB3, PDE6H, PDE6C, GNAT2, and ATF6. ATF6 is the most recent gene to be identified, though thorough phenotyping of this genetic subtype is lacking. Here, we sought to test the hypothesis that ATF6-associated ACHM is a structurally distinct form of congenital ACHM. Methods: Seven genetically confirmed subjects from five nonconsanguineous families were recruited. Foveal hypoplasia and the integrity of the ellipsoid zone (EZ) band (a.k.a., IS/OS) were graded from optical coherence tomography (OCT) images. Images of the photoreceptor mosaic were acquired using confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Parafoveal cone and rod density values were calculated and compared to published normative data as well as data from two subjects harboring CNGA3 or CNGB3 mutations who were recruited for comparative purposes. Additionally, nonconfocal dark-field AOSLO images of the retinal pigment epithelium were obtained, with quantitative analysis performed in one subject with ATF6-ACHM. Results: Foveal hypoplasia was observed in all subjects with ATF6 mutations. Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects with ATF6 using OCT. There was no evidence of remnant foveal cone structure using confocal AOSLO, although sporadic cone-like structures were seen in nonconfocal split-detection AOSLO. There was a lack of cone structure in the parafovea, in direct contrast to previous reports. Conclusions: Our data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6-ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3- or CNGB3-ACHM.