Monochromacy Research Articles

The Independent Yellow Channel For Tetrachromatic Imaging

Imaging systems tend at first to simulate the opponent yellow and blue vision channels (YB) even if that perceptibly violates trichromatic simulation of opponent red and green channels (RG). The preference is biologically traced: 8% male population are deficient in RG vision and only 0.003% in YB vision. The YB pair is not the usually assumed alternating combination of M, L, and S-cone responses (say, L+M-S): it is independent of RG sensations (L-M). The complementary yellow (570) and blue (465 nm) are seen after the RG pair has disappeared with decreasing illumination. The yellow is not seen after the 650-nm sensitivity limit of rhodopsin even if the red is over 50 nm more. The ‘blue-cone monochromats’ and some protanopes, having no M and L-cones, see the YB pair. Yellow adaptation eliminates the YB sensations but hardly influences the RG pair. Reflectometry of living retinas shows the ‘M and S-cone pigments’ rather to be long-living products of iodopsin (L-pigment) and rhodopsin.

Motion perception at scotopic light levels

Although the spatial and temporal properties of rod-mediated vision have been extensively characterized, little is known about scotopic motion perception. To provide such information, we determined thresholds for the detection and identification of the direction of motion of sinusoidal grating patches moving at speeds from 1 to 32 deg/s, under scotopic light levels, in four different types of observers: three normals, a rod monochromat (who lacks all cone vision), an S-cone monochromat (who lacks M- and L-cone vision), and four deuteranopes (who lack M-cone vision). The deuteranopes, whose motion perception does not differ from that of normals, allowed us to measure rod and L-cone thresholds under silent substitution conditions and to compare directly the perceived velocity for moving stimuli detected by either rod or cone vision at the same light level. We find, for rod as for cone vision, that the direction of motion can be reliably identified very near to detection threshold. In contrast, the perceived velocity of rod-mediated stimuli is reduced by approximately 20% relative to cone-mediated stimuli at temporal frequencies below 4 Hz and at all intensity levels investigated (0.92 to -1.12 log cd m(-2)). Most likely, the difference in velocity perception is distal in origin because rod and cone signals converge in the retina and further processing of their combined signals in the visual cortex is presumably identical. To account for the difference, we propose a model of velocity, in which the greater temporal averaging of rod signals in the retina leads to an attenuation of the motion signal in the detectors tuned to high velocities.

Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy

Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy

Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy.

Blue cone monochromacy (BCM) is an X-linked ocular disease characterized by poor visual acuity, nystagmus, and photodysphoria in males with severely reduced color discrimination. Deletions, rearrangements and point mutations in the red and green pigment genes have been implicated in causing BCM. We assessed the spectrum of genetic alterations in ten families with BCM by Southern blot, polymerase chain reaction, and sequencing analysis, and the phenotype was characterized by ophthalmoscopy, fluorescein angiography, and a battery of tests to assess color vision in addition to routine ophthalmological examination. All families showed clinical features associated with BCM. Acuities were reduced in all affected males, and photopic b-wave was reduced by more than 90% in seven families. In three families, however, the photopic b-wave response showed uncharacteristic relative preservation of 30-80% (of the clinical low-normal value). The color vision was unusually preserved in two affected males, but this was not correlated with photopic electroretinography retention. Progressive macular atrophy was observed in affected members of two BCM families while the rest of the families presented with normal fundus. In nine families deletions were identified in the gene encoding the red-sensitive photopigment and/or in the region up to 17.8 kb upstream of the red gene which contains the locus control region and other regulatory sequences. In the same nine families the red pigment gene showed a range of deletions from the loss of a single exon to loss of the complete red gene. In one family no mutation was found in the exons of the red gene or the locus control region but showed loss of the complete green gene. No association was observed between the phenotypes and genotypes in these families.

Genetic basis of total colourblindness among the Pingelapese islanders.

Complete achromatopsia is a rare, autosomal recessive disorder characterized by photophobia, low visual acuity, nystagmus and a total inability to distinguish colours. In this disease, cone photoreceptors, the retinal sensory neurons mediating colour vision, seem viable but fail to generate an electrical response to light. Achromatopsia, or rod monochromatism, was first mapped to 2p11-2q12 (MIM 216900; ref. 3), where it is associated with missense mutations in CNGA3 (ref. 4). CNGA3 encodes the alpha-subunit of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A second locus at 8q21-q22 has been identified among the Pingelapese islanders of Micronesia, who have a high incidence of recessive achromatopsia (MIM 262300). Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel. Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3. Combined with earlier findings, our results demonstrate that both alpha- and beta-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

Manifestations of rod monochromacy

Rod monochromacy or total color blindness is a rare autosomal recessively inherited disorder. In a high percentage of individuals, it is caused by mutations in the CNGA3 gene, which encodes the α-subunit of the cone photoreceptor cGMP-gated cation channel. We assessed visual function in affected individuals with homozygous and compound heterozygous mutations and in heterozygous carriers in families carrying different mutations in the CNGA3 gene. Our psychophysical and electroretinographic tests demonstrate that the severity of rod monochromacy depends upon the nature and combination of the mutations in the CNGA3 gene. © 2000 John Wiley & Sons, Inc. Col Res Appl, 26, S96–S99, 2001

Electroretinograms in S-cone monochromacy using S-cone and rod isolating stimuli

To study the electrophysiological properties of the S-cone pathway, we adopted a silent substitution paradigm for ERG measurements in an S-cone (blue-cone) monochromat. ERG responses to pure S-cone and rod square wave modulation were measured for different temporal frequencies (1–36 Hz) at 66 cd/m2 mean luminance and additionally to 1 and 12 Hz modulation at 6.6 cd/m2 mean luminance. We found rod ERG signals up to a temporal frequency of 30 Hz and S-cone ERG signals up to 36 Hz. For 1 and 2 Hz temporal modulation, the S-cone ERG showed a negative deflection after stimulus onset and a positive deflection (OFF-response) after stimulus offset, whereas for the rod ERG the reverse was the case. At temporal modulations of 6 Hz and above, the first harmonic response showed a phase difference between S-cone and rod modulation of about 180°. The S-cone ERG response amplitude for frequencies above 12 Hz with similar photoreceptor contrast was larger than the rod ERG response amplitude. At the lower mean luminance (6.6 cd/m2), the response amplitude of the S-cone-ERG was smaller than that found at the higher mean luminance (66 cd/m2), whereas the rod ERG response was larger. The response phase of the S-cone ERG lagged compared to that at the higher mean luminance (66 cd/m2), whereas the rod ERG response was phase advanced. Our approach can serve as a method to detect differences between the rod and S-cone pathways and to evaluate protocols of the human S-cone ERG. © 2000 John Wiley & Sons, Inc. Col Res Appl, 26, S136–S139, 2001

Homozygosity Mapping of the Achromatopsia Locus in the Pingelapese

Achromatopsia, or total color blindness (also referred to as "rod monochromacy"), is a severe retinal disorder characterized clinically by an inability to distinguish colors, impaired visual acuity in daylight, photophobia, and nystagmus. Inherited as an autosomal recessive trait, achromatopsia is rare in the general population (1:20,000-1:50,000). Among the Pingelapese people of the Eastern Caroline Islands, however, the disorder occurs at an extremely high frequency, as recounted in Oliver Sacks's popular book The Island of the Colorblind: 4%-10% of this island population have the disorder and approximately 30% carry the gene. This extraordinary enrichment of the disease allele most likely resulted from a sharp reduction in population in the late 18th century, in the aftermath of a typhoon and subsequent geographic and cultural isolation. To obtain insights into the genetic basis of achromatopsia, as well as into the genetic history of this region of Micronesia, a genomewide search for linkage was performed in three Pingelapese kindreds with achromatopsia. A two-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified on 8q21-q22. A maximal multipoint LOD score of 9.5 was observed with marker D8S1707. Homozygosity was seen for three adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease-gene locus that spans a distance of <6.5cM.

The spectral sensitivity of the human short-wavelength sensitive cones derived from thresholds and color matches

We used two methods to estimate short-wave (S) cone spectral sensitivity. Firstly, we measured S-cone thresholds centrally and peripherally in five trichromats, and in three blue-cone monochromats, who lack functioning middle-wave (M) and long-wave (L) cones. Secondly, we analyzed standard color-matching data. Both methods yielded equivalent results, on the basis of which we propose new S-cone spectral sensitivity functions. At short and middle-wavelengths, our measurements are consistent with the color matching data of Stiles and Burch (1955, Optica Acta, 2, 168–181; 1959, Optica Acta, 6, 1–26), and other psychophysically measured functions, such as π 3 (Stiles, 1953, Coloquio sobre problemas opticos de la vision, 1, 65–103). At longer wavelengths, S-cone sensitivity has previously been over-estimated.

Rods induce transient tritanopia in blue cone monochromats.

Transient tritanopia is a cone-cone post-receptoral interaction between short-wavelength (S) cones and medium (M) and long (L) wavelength cones. Blue cone monochromats have rods and S cones of normal sensitivity but lack functional M/L cones. All blue cone monochromats tested (n = 8) show significant amounts of transient tritanopia mediated by rods. Attempts to find a similar rod-S cone interaction while silencing the L/M cones in normals yielded only a small amount of S cone sensitivity loss. The results suggest an exaggerated influence of rods on the S cone pathway in the retina of blue cone monochromats.

Congenital Motor Nystagmus Linked to Xq26-q27

Congenital motor nystagmus (CMN) is a hereditary disorder characterized by bilateral ocular oscillations that begin in the first 6 mo of life. It must be distinguished from those genetic disorders-such as ocular albinism (OA), congenital stationary night blindness (CSNB), and blue-cone monochromatism (BCM)-in which nystagmus accompanies a clinically apparent defect in the visual sensory system. Although CMN is presumed to arise from a neurological abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Three families with CMN inherited in an X-linked, irregularly dominant pattern were investigated with linkage and candidate gene analysis. The penetrance among obligate female carriers was 54%. Evaluation of markers in the region of the genes for X-linked OA, CSNB, and BCM revealed no evidence of linkage, supporting the hypothesis that CMN represents a distinct entity. The gene was mapped to chromosome Xq26-q27 with the following markers: GATA172D05 (LOD score 3.164; recombination fraction [theta] = 0.156), DXS1047 (LOD score 10.296; theta = 0), DXS1192 (LOD score 8.174; theta = 0.027), DXS1232 (LOD score 6.015; theta = 0.036), DXS984 (LOD score 6.695; theta = 0), and GATA31E08 (LOD score 4.940; theta = 0.083). Assessment of haplotypes and multipoint linkage analysis, which gave a maximum LOD score of 10.790 with the 1-LOD-unit support interval spanning approximately 7 cM, place the gene in a region between GATA172D05 and DXS1192. Evaluation of candidate genes CDR1 and SOX3 did not reveal mutations in affected male subjects.

Is the rod visual field temporally homogeneous?

Cone vision has been shown to be temporally inhomogeneous across the visual field. In the periphery, contrast sensitivity is lower for low temporal frequencies and higher for high temporal frequencies. Here we ask a similar question for rod vision at mesopic luminances. Isolation is obtained by testing a well documented rod monochromat. We show that the rod visual field exhibits only a modest degree of temporal inhomogeneity.

Human cone spectral sensitivities: a progress report

The spectral sensitivities of the short (S-), middle (M-) and long (L-) wave-sensitive cones have been measured in normal trichromats and in dichromats and monochromats of known genotype. For the S-cone sensitivities, three blue-cone monochromats and five normals were used; for the M-cone sensitivities, nine protanopes (three with a single L1M2 gene, three with a single L2M3 gene, one with both an L1M2 and an M gene, and two with both an L2M3 and an M gene); and for the L-cone sensitivities, 22 deuteranopes (five with a single L(ala 180) gene and 17 with a single L(ser 180) gene). We compare existing cone spectral sensitivity estimates with these results and with tritanopic color matches. The new findings are more consistent with the cone fundamentals of Stockman et al. (JOSA 1993(A10), 2491) than with those of Smith and Pokorny (Vision Research 1975(15), 161). The discrepancies that we find, however, are sufficient to warrant the replacement of both sets.

Human Rod Monochromacy: Linkage Analysis and Mapping of a Cone Photoreceptor Expressed Candidate Gene on Chromosome 2q11

We have performed linkage analysis in eight families with rod monochromacy, an autosomal recessively inherited condition with complete color blindness. Significant linkage was found with markers located at the pericentromeric region of chromosome 2. A maximum lod score of 5.36 was obtained for marker D2S2333 at θ = 0.00. Mapping of meiotic breakpoints localized the disease gene between markers D2S2187 and D2S2229. Homozygosity for a number of subsequent markers indicating identity by descent was found in two families and provides evidence for a further refinement of the locus proximal to D2S373. This defines an interval of ≈3 cM covering theACHM2locus for rod monochromacy. Radiation hybrid mapping of theCNGA3gene encoding the α-subunit of the cGMP gated cation channel in human cone photoreceptors resulted in a maximum lod score of 16.1 with marker D2S2311 combined with a calculated physical distance of 6.19cR10,000. Screening of the CEPH YAC library and subsequent STS mapping indicated the physical order cen–D2S2222–D2S2175–(D2S2187/D2S2311)–qtel ofmarkers on 2q11 and showed that theCNGA3gene maps most closely to D2S2187 and D2S2311. These data indicate that theCNGA3gene maps within the critical interval of theACHM2locus for rod monochromacy and thus is a candidate gene for this disease.

Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel.

Total colourblindness (OMIM 216900), also referred to as rod monochromacy (RM) or complete achromatopsia, is a rare, autosomal recessive inherited and congenital disorder characterized by photophobia, reduced visual acuity, nystagmus and the complete inability to discriminate between colours. Electroretinographic recordings show that in RM, rod photoreceptor function is normal, whereas cone photoreceptor responses are absent. The locus for RM has been mapped to chromosome 2q11 (ref. 2), however the gene underlying RM has not yet been identified. Recently, a suitable candidate gene, CNGA3, encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel, a key component of the phototransduction pathway, has been cloned and assigned to human chromosome 2q11 (refs 3,4). We report the identification of missense mutations in CNGA3 in five families with RM. Homozygous mutations are present in two families, whereas the remaining families show compound heterozygous mutations. In all cases, the segregation pattern of the mutations is consistent with the autosomal recessive inheritance of the disease and all mutations affect amino acids that are highly conserved among cyclic nucleotide gated channels (CNG) in various species. This is the first report of a colour vision disorder caused by defects other than mutations in the cone pigment genes, and implies at least in this instance a common genetic basis for phototransduction in the three different cone photoreceptors of the human retina.

Photopigments and photoentrainment in the Syrian golden hamster

The Syrian golden hamster ( Mesocricetus auratus) is an important model in the study of circadian rhythms. However, as in other mammals, little is known about the photoreceptors that mediate circadian entrainment. Using immunocytochemistry and RNA blot hybridization, we found no evidence for the presence of blue-/UV-sensitive opsin. In contrast, green-sensitive cone opsin was demonstrated in the retina both by immunocytochemistry and reverse-transcription PCR. When used as a probe in RNA blot hybridization, this PCR fragment labelled one transcript (5.8 kb) in hamster retinal RNA. These findings are in accordance with preliminary data from other investigators using electroretinography, which showed one cone-mediated photoreceptive mechanism with a maximum sensitivity of 501 nm, but none at shorter wavelengths. However, we found that non-saturating pulses of ultraviolet radiation (357 nm) caused phase shifts in locomotor behaviour. These results corroborate earlier reports that UV radiation can regulate the photoperiodic response in this animal. Having confirmed these apparently contradictory earlier reports, we discuss the mechanisms that might create a UV-triggered non-visual response in a green cone monochromat. Finally, we propose the use of the Syrian golden hamster as a model for photoreceptor development and function in the absence of S/UV cones.

Submicrovolt full-field cone electroretinograms: artifacts and reproducibility.

The clinical utility of submicrovolt full-field 30-Hz (cone) electroretinograms was assessed by quantifying their contamination by electrical and photoelectric artifacts from xenon-flash stimulators and their test-retest variation in patients with retinitis pigmentosa. Artifacts obtained in saline with four commonly used electrodes varied with electrode type and consisted of an early, brief electrical component and a superimposed, extended photoelectric component. Techniques for minimizing these artifacts are described. Electroretinogram recordings from patients with advanced retinitis pigmentosa or congenital rod monochromatism indicate that these artifacts can be virtually eliminated with bipolar lenses. To assess test-retest variation, narrow-band-filtered responses were obtained twice during 6 weeks from patients with amplitudes less than 1 microV; threshold criteria for significant (p < 0.05) change in amplitude with this technique were approximately 0.25 log unit for each of two different systems.

EMG responses to air splint application in children with cerebral palsy

The spectral sensitivities of the short (S-), middle (M-) and long (L-) wave-sensitive cones have been measured in normal trichromats and in dichromats and monochromats of known genotype. For the S-cone sensitivities, three blue-cone monochromats and five normals were used; for the M-cone sensitivities, nine protanopes (three with a single L1M2 gene, three with a single L2M3 gene, one with both an L1M2 and an M gene, and two with both an L2M3 and an M gene); and for the L-cone sensitivities, 22 deuteranopes (five with a single L(ala180) gene and 17 with a single L(ser180) gene). We compare existing cone spectral sensitivity estimates with these results and with tritanopic color matches. The new findings are more consistent with the cone fundamentals of Stockman et al. (JOSA 1993(A10), 2491) than with those of Smith and Pokorny (Vision Research 1975(15), 161). The discrepancies that we find, however, are sufficient to warrant the replacement of both sets.

Gene Conversion between Red and Defective Green Opsin Gene in Blue Cone Monochromacy

Blue cone monochromacy is an X-linked condition in which the function of both the red pigment gene (RCP) and the green pigment gene (GCP) is impaired. Blue cone monochromacy can be due to a red/green gene array rearrangement existing of a single red/green hybrid gene and an inactivating C203R point mutation in GCP. We describe here a family with blue cone monochromacy due to the presence of the C203R mutation in both RCP and GCP. The flanking sequences of the C203R mutation in exon 4 of RCP were characteristic for GCP, indicating that this mutation was transferred from GCP into RCP by gene conversion.

Surgical Dampening of Nystagmus in Patients with Achromatopsia

Lack of cone function is one and nystagmus is the other cause of low vision in patients with rod monochromatism. The nystagmus has been assumed to be a consequence of the increased light sensitivity due to the predominance of rods. However, symptoms of patients with cone dystrophy are not very different from those observed in patients with congenital nystagmus. For example, they occasionally have a dampening of the nystagmus on fixation at near. Therefore, like in congenital nystagmus, we can elicit convergence innervation during fixation at distance with prisms base-out or with a surgically induced divergence ('artificial divergence'). This approach only works in patients with binocular function, necessary to keep the eyes aligned. The authors report on three patients with complete rod monochromatism in whom they performed an artificial divergence operation (OAD) by recessing the medial rectus muscle and resecting the lateral muscle of one eye. After surgery, the measured visual acuity was the same but the nystagmus of these patients had been considerably reduced. The patients themselves considered the effect of surgery a great improvement.