Herbert Jägle | Regensburg University of Applied Sciences (original) (raw)
Papers by Herbert Jägle
European Journal of Human Genetics, 2005
Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack o... more Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (o0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.
American Journal of Human Genetics, 2001
We recently showed that mutations in the CNGA3 gene encoding the a-subunit of the cone photorecep... more We recently showed that mutations in the CNGA3 gene encoding the a-subunit of the cone photoreceptor cGMPgated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all detected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Scandinavia and northern Italy, have a common origin.
Journal of Vision, 2006
We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with... more We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelengthsensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L-or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of LYM cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.
Journal of Vision, 2002
Multifocal electroretinograms (mfERG) were recorded from 38 normal trichromats with a pattern-rev... more Multifocal electroretinograms (mfERG) were recorded from 38 normal trichromats with a pattern-reversing display that modulated only their long-wavelength sensitive (L) or only their middle-wavelength sensitive (M) cones at equal cone contrasts and average quantal catches. The display consisted of scaled, 103 hexagonal elements, subtending 84° x 75° of visual angle. Typically, the amplitude of the L-cone driven signal was greater than that for the M-cone driven one at all retinal eccentricities, but large differences were found among observers. These values correlated with L-to M-cone ratios obtained psychophysically in the same observers using 2° (dia.) heterochromatic flicker photometry. Interestingly, the L-to M-cone driven amplitude ratios differed between the central and peripheral retina. For the central fovea (5° dia.), the mean ratio was 1.4 ± 0.6 (for the N1P1 component), whereas for the annular ring centered at 40° in the periphery, it was 2.3 ± 2.0. The mean P1 latency of the summed M-cone driven mfERG (28.0 ± 2.6 ms) was significantly advanced relative to the L-cone driven signal (29.0 ± 1.9 ms), but the mean N1 latencies were similar (15.6 ± 1.7 ms and 16.2 ± 1.3 ms, respectively). The P1 latency difference between the L-and M-cone driven waveforms was not found in the central 5° (dia.) of the retina. However, it increased with retinal eccentricity. The regional differences in the amplitudes and latencies of the L-and M-cone driven mfERG signals can be related to variations in the L-to M-cone ratios and/or the receptor to bipolar gain factors that depend on eccentricity.
Human Molecular Genetics, 2002
We investigated the genotypic variation in 50 red-green color vision deficient males (27 deuteran... more We investigated the genotypic variation in 50 red-green color vision deficient males (27 deuteranopes and 23 protanopes) of middle European ancestry who possess multiple genes in the X-linked photopigment gene array. We have previously shown that only the first two genes of the array are expressed and contribute to the color vision phenotype. Therefore, the hypothesis is that the first two genes possessed by multigene-dichromats encode pigments of identical or nearly identical spectral sensitivity: one gene normal (R or G) and the other a hybrid (G/R or R/G). The spectral sensitivities of the encoded pigments were inferred from published in vitro and in vivo data. The color vision phenotype was assessed by standard anomaloscopy. Most genotypes (92%) included hybrid genes whose sequence and position and whose encoded pigment correlated exactly with the phenotype. However, one and possibly two of the protanopes had gene arrays consistent with protanomaly rather than protanopia, since two spectrally different pigments may be encoded by their arrays. Two of the deuteranopes had only R-and G-photopigment genes, without any detectable G/R-hybrid genes or any as-of-yet identified point mutation or coding/promoter sequence deletions. Further, an unexpectedly high number of multigene-deuteranopes (11%) had the C203R mutation in their most upstream G-pigment gene, suggesting a founder effect of middle European origin for this mutation. About half of the protanopes possessed an upstream R/G-hybrid gene with different exon 2 coding sequences than their downstream G-pigment gene(s), which is inconsistent with published data implying that a single amino acid substitution in exon 2 can confer red-green color discrimination capacity on multigene-protans by altering the optical density of the cones.
Visual Neuroscience, 2004
The aim of this study was to obtain information about single cone class driven activity in the in... more The aim of this study was to obtain information about single cone class driven activity in the inner and outer retina in humans. We examined outer retinal activity with the multifocal electroretinogram (mfERG) and inner retinal activity using multifocal oscillatory potentials (mfOPs). A standard (black-white) stimulus was used, as well as stimuli aimed at isolating a single photoreceptor class. The results of 10 trichromats were compared to those of 2 protanopes and 2 deuteranopes. At both retinal layers we find that trichromats show cone isolating response amplitudes that reflect the expected number of cones and that single- gene dichromats have a similar total number of functioning cones as trichromats. The ratio of the responses of the L- and M-cones is slightly smaller for the mfOPs than for the mfERGs. The results indicate that there are major changes in the gain of retinal signals after the inner plexiform layer.
We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with... more We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelengthsensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L-or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of LYM cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.
Journal of Vision, 2005
We propose a new luminosity function, V Ã ð1Þ, that improves upon the original CIE 1924 Vð1Þ func... more We propose a new luminosity function, V Ã ð1Þ, that improves upon the original CIE 1924 Vð1Þ function and its modification by D. and J. J. , while being consistent with a linear combination of the A. Stockman & L. T. Sharpe long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone fundamentals. It is based on experimentally determined 25 Hz, 2-diameter, heterochromatic (minimum) flicker photometric data obtained from 40 observers (35 males, 5 females) of known genotype, 22 with the serine variant L(ser180), 16 with the alanine L(ala180) variant, and 2 with both variants of the L-cone photopigment. The matches, from 425 to 675 nm in 5-nm steps, were made on a 3 log troland xenon white (correlated color temperature of 5586 K but tritanopically metameric with CIE D 65 standard daylight for the Stockman and Sharpe L-and M-cone fundamentals in quantal units) adapting field of 16-angular subtense, relative to a 560-nm standard. Both the reference standard and test lights were kept near flicker threshold so that, in the region of the targets, the total retinal illuminance averaged 3.19 log trolands. The advantages of the new function are as follows: it forms a consistent set with the new proposed CIE cone fundamentals (which are the Stockman & Sharpe 2000 cone fundamentals); it is based solely on flicker photometry, which is the standard method for defining luminance; it corresponds to a central 2-viewing field, for which the basic laws of brightness matching are valid for flicker photometry; its composition of the serine/alanine L-cone pigment polymorphism (58:42) closely matches the reported incidence in the normal population (56:44; Stockman & Sharpe, 1999); and it specifies luminance for a reproducible, standard daylight condition. V Ã ð1Þ is defined as 1:55Lð1Þ þ Mð1Þ, where Lð1Þ and Mð1Þ are the Stockman & Sharpe L-& M-cone (quantal) fundamentals. It is extrapolated to wavelengths shorter than 425 nm and longer than 675 nm using the Stockman & Sharpe cone fundamentals.
Graefes Archive for Clinical and Experimental Ophthalmology, 2006
Purpose To study the electroretinographic signals originating in the long-wavelength-sensitive (L... more Purpose To study the electroretinographic signals originating in the long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone pathways by means of large-field and multifocal cone type-specific electroretinograms (ERGs) in a patient with progressive cone dystrophy. Methods A 65-year-old male patient with colour vision disturbances (age at onset 10 years), loss of visual acuity (14 years), and central visual field defects (40 years) was investigated. Large-field flicker-ERG responses to stimuli that exclusively modulated the L-cones or the M-cones, or the two simultaneously (both in-phase and in counter-phase), were measured. Short-wavelength-sensitive (S) cones were not modulated. Multifocal ERGs (mfERGs) were also recorded, with a pattern-reversing display that modulated only the L- or the M-cones at equal cone contrasts and average quantal catches. Genetic analysis of L- and M-pigment genes was performed on genomic DNA isolated from peripheral venous blood. Results The patient showed a normal rod-driven ERG but reduced cone-driven electroretinographic amplitudes with normal implicit times in the International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERG. The large-field flicker-ERG responses to pure L-cone modulation were significantly above noise level but were substantially reduced in comparison with both normal trichromatic subjects and (otherwise normal) deuteranopes. The L-cone driven electroretinographic implicit times and phases were within normal limits. The M-cone driven electroretinographic responses were not detectable. A model fit of all the L- and M-cone driven flicker-ERG data revealed that the responses were exclusively driven by the L-cones. Consistently, the cone type-specific mfERGs showed severely reduced but detectable responses to L-cone-isolating stimuli. The M-cone driven multifocal-ERG responses were undistinguishable from noise. The L- and M-pigment gene array consisted of only a single L-pigment gene. The complete coding sequence of this gene was determined and showed no abnormality. Conclusions This patient exhibits a coincidence of progressive cone dystrophy and deuteranopia. The molecular genetic data of the L/M-pigment gene array is consistent with the deutan phenotype. It cannot be excluded that the rearrangement of the X-chromosome pigment gene array is responsible for the cone dystrophy in this patient. It is, however, suggested that the dichromacy and the cone dystrophy have different and independent genetic origins.
Vision Research, 2003
Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal wh... more Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In ''flecked retina diseases'' heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance.
PURPOSE. Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized... more PURPOSE. Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior results. METHODS. Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. RESULTS. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS. The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.
Nature Genetics, 1998
Total colourblindness (OMIM 216900), also referred to as rod monochromacy (RM) or complete achrom... more 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.
Investigative Ophthalmology & Visual Science, 2008
Journal of Vision, 2002
Multifocal visual evoked potentials (mfVEP) were recorded with a pattern-reversing display that m... more Multifocal visual evoked potentials (mfVEP) were recorded with a pattern-reversing display that modulated only the long wavelength-sensitive (L) cones or only the middle wavelength-sensitive (M) cones. Outside the central 5.8° (radius), the ratio of the amplitudes of the mfVEP responses to L-and M-cone modulation varied across the six subjects, ranging from 1.1 to 1.7. The responses from the central 1° (radius) showed a substantially lower ratio, ranging from 0.8 to 1.1 (average of 0.9). The variation among individuals outside the central fovea is probably due to differences in the ratio of the L/M cone input to both magno-and parvocellular pathways. The substantially lower ratios for the central responses is consistent with an L/M cone ratio closer to 1.0 in the central 1° and/or an adjustment in the gain of the L-versus M-cone contributions to the central parvocellular pathways. Taking into consideration evidence from other techniques, we believe it is unlikely that most individuals have a L/M cone ratio of 1.0 in the fovea. Instead, it appears that there is a change in gain before the mfVEP is generated in area 17.
Nature Neuroscience, 2002
We describe a compelling demonstration of large-scale developmental reorganization in the human v... more We describe a compelling demonstration of large-scale developmental reorganization in the human visual pathways. The developmental reorganization was observed in rod monochromats, a rare group of congenitally colorblind individuals who virtually lack cone photoreceptor function. Normal controls had a cortical region, spanning several square centimeters, that responded to signals initiated in the all-cone foveola but was inactive under rod viewing conditions; in rod monochromats this cortical region responded powerfully to rod-initiated signals. The measurements trace a causal pathway that begins with a genetic anomaly that directly influences sensory cells and ultimately results in a substantial central reorganization.
Documenta Ophthalmologica, 2006
The relative number of L- and M-cones varies greatly between individuals. Differences in the rela... more The relative number of L- and M-cones varies greatly between individuals. Differences in the relative number of L- and M-cones may also contribute to the sex difference in the ERG response amplitude reported several times. We therefore investigated the relative number of L- and M-cones and its impact on sex differences in ERG amplitudes. Multifocal ERG (mfERG) and multifocal oscillatory potentials (mfOP) combined with a cone silent substitution technique were used to investigate outer and inner retinal signals recorded from 7 female and 7 male trichromats. L:M ratios were estimated from peak amplitude as well as from area under curve (AUC) analysis. For mfERGs the L:M ratios estimates were independent of the method of analysis, while for mfOPs, differences were found which are possibly due to an artefact in the calculation of ratios for small responses. There was a tendency for lower L:M ratios in female than in male subjects for both analysis of mfERG and mfOP responses. The (L+M)-response amplitudes at both sites were slightly higher and the L:M ratios were lower for female than for male observers. Because the magnitude of the ERG amplitude differences is larger than could be explained by L:M-ratio and axial length differences, we conclude that it may be due to a direct effect of sex hormones on ion channel function.
Graefes Archive for Clinical and Experimental Ophthalmology, 2005
Background The Nagel anomaloscope Model I is the definitive clinical instrument for classifying p... more Background The Nagel anomaloscope Model I is the definitive clinical instrument for classifying phenotypic variations in X-linked color-vision disorders. Its system of classification is based on the Rayleigh equation: the relative amounts of red and green primary lights required to match a yellow primary. Our aim was to characterize how changes in mains voltage and ambient temperature influence the wavelength and intensity of each primary and alter the Rayleigh matches of normal and anomalous trichromats. Methods A Nagel Model I anomaloscope was calibrated in wavelength and intensity while varying the temperature of its prism housing and the mains voltage. Three normal, three protanomalous and three deuteranomalous trichromats made Rayleigh matches at various temperatures and voltages. Results The intensities of the green and red primaries show an exponential growth with mains voltage. Additionally, the wavelengths and intensities of all three primaries change with prism housing temperature. As a result, the R-G match midpoints of normal and anomalous trichromats shift with increasing mains voltage, and more markedly with increasing prism housing temperature, to higher R-G settings. Conclusions Rayleigh matches obtained with the Nagel I anomaloscope are sensitive to changes in voltage supply and prism housing temperature, arising largely from thermal effects of the internal light sources. However, the instrument may still be safely used for diagnostic and research purposes provided that: (1) a stable voltage supply is used; (2) it is kept at a constant temperature; and (3) the match midpoint of the reference population has been established under identical conditions.
Vision Research, 1999
Using heterochromatic flicker photometry, we have measured the corneal spectral sensitivities of ... more Using heterochromatic flicker photometry, we have measured the corneal spectral sensitivities of the X-chromosome-linked photopigments in 40 dichromats, 37 of whom have a single opsin gene in their tandem array. The photopigments encoded by their genes include: the alanine variant of the normal middle-wavelength sensitive photopigment, M(A180); the alanine and serine variants of the normal long-wavelength sensitive photopigment, L(A180) and L(S180); four different L -M hybrid or anomalous photopigments, L2M3(A180), L3M4(S180), L4M5(A180) and L4M5(S180); and two variants of the L-cone photopigment, encoded by genes with embedded M-cone exon two sequences, L(M2; A180) and L(M2; S180). The peak absorbances (u max ) of the underlying photopigment spectra associated with each genotype were estimated by correcting the corneal spectral sensitivities back to the retinal level, after removing the effects of the macular and lens pigments and fitting a template of fixed shape to the dilute photopigment spectrum. Details of the genotype-phenotype correlations are summarized elsewhere (Sharpe, L. T., Stockman, A., Jägle, H., Knau, H., Klausen, G., Reitner, A. et al. (1998). J. Neuroscience, 18, 10053 -10069). Here, we present the individual corneal spectral sensitivities for the first time as well as details and a comparison of three analyses used to estimate the u max values, including one in which the lens and macular pigment densities of each observer were individually measured.
American Journal of Ophthalmology, 2004
PURPOSE: To investigate short-term visual effects of a single 100-mg dose of Viagra (sildenafil c... more PURPOSE: To investigate short-term visual effects of a single 100-mg dose of Viagra (sildenafil citrate) in healthy men.
European Journal of Human Genetics, 2005
Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack o... more Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (o0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.
American Journal of Human Genetics, 2001
We recently showed that mutations in the CNGA3 gene encoding the a-subunit of the cone photorecep... more We recently showed that mutations in the CNGA3 gene encoding the a-subunit of the cone photoreceptor cGMPgated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all detected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Scandinavia and northern Italy, have a common origin.
Journal of Vision, 2006
We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with... more We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelengthsensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L-or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of LYM cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.
Journal of Vision, 2002
Multifocal electroretinograms (mfERG) were recorded from 38 normal trichromats with a pattern-rev... more Multifocal electroretinograms (mfERG) were recorded from 38 normal trichromats with a pattern-reversing display that modulated only their long-wavelength sensitive (L) or only their middle-wavelength sensitive (M) cones at equal cone contrasts and average quantal catches. The display consisted of scaled, 103 hexagonal elements, subtending 84° x 75° of visual angle. Typically, the amplitude of the L-cone driven signal was greater than that for the M-cone driven one at all retinal eccentricities, but large differences were found among observers. These values correlated with L-to M-cone ratios obtained psychophysically in the same observers using 2° (dia.) heterochromatic flicker photometry. Interestingly, the L-to M-cone driven amplitude ratios differed between the central and peripheral retina. For the central fovea (5° dia.), the mean ratio was 1.4 ± 0.6 (for the N1P1 component), whereas for the annular ring centered at 40° in the periphery, it was 2.3 ± 2.0. The mean P1 latency of the summed M-cone driven mfERG (28.0 ± 2.6 ms) was significantly advanced relative to the L-cone driven signal (29.0 ± 1.9 ms), but the mean N1 latencies were similar (15.6 ± 1.7 ms and 16.2 ± 1.3 ms, respectively). The P1 latency difference between the L-and M-cone driven waveforms was not found in the central 5° (dia.) of the retina. However, it increased with retinal eccentricity. The regional differences in the amplitudes and latencies of the L-and M-cone driven mfERG signals can be related to variations in the L-to M-cone ratios and/or the receptor to bipolar gain factors that depend on eccentricity.
Human Molecular Genetics, 2002
We investigated the genotypic variation in 50 red-green color vision deficient males (27 deuteran... more We investigated the genotypic variation in 50 red-green color vision deficient males (27 deuteranopes and 23 protanopes) of middle European ancestry who possess multiple genes in the X-linked photopigment gene array. We have previously shown that only the first two genes of the array are expressed and contribute to the color vision phenotype. Therefore, the hypothesis is that the first two genes possessed by multigene-dichromats encode pigments of identical or nearly identical spectral sensitivity: one gene normal (R or G) and the other a hybrid (G/R or R/G). The spectral sensitivities of the encoded pigments were inferred from published in vitro and in vivo data. The color vision phenotype was assessed by standard anomaloscopy. Most genotypes (92%) included hybrid genes whose sequence and position and whose encoded pigment correlated exactly with the phenotype. However, one and possibly two of the protanopes had gene arrays consistent with protanomaly rather than protanopia, since two spectrally different pigments may be encoded by their arrays. Two of the deuteranopes had only R-and G-photopigment genes, without any detectable G/R-hybrid genes or any as-of-yet identified point mutation or coding/promoter sequence deletions. Further, an unexpectedly high number of multigene-deuteranopes (11%) had the C203R mutation in their most upstream G-pigment gene, suggesting a founder effect of middle European origin for this mutation. About half of the protanopes possessed an upstream R/G-hybrid gene with different exon 2 coding sequences than their downstream G-pigment gene(s), which is inconsistent with published data implying that a single amino acid substitution in exon 2 can confer red-green color discrimination capacity on multigene-protans by altering the optical density of the cones.
Visual Neuroscience, 2004
The aim of this study was to obtain information about single cone class driven activity in the in... more The aim of this study was to obtain information about single cone class driven activity in the inner and outer retina in humans. We examined outer retinal activity with the multifocal electroretinogram (mfERG) and inner retinal activity using multifocal oscillatory potentials (mfOPs). A standard (black-white) stimulus was used, as well as stimuli aimed at isolating a single photoreceptor class. The results of 10 trichromats were compared to those of 2 protanopes and 2 deuteranopes. At both retinal layers we find that trichromats show cone isolating response amplitudes that reflect the expected number of cones and that single- gene dichromats have a similar total number of functioning cones as trichromats. The ratio of the responses of the L- and M-cones is slightly smaller for the mfOPs than for the mfERGs. The results indicate that there are major changes in the gain of retinal signals after the inner plexiform layer.
We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with... more We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelengthsensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L-or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of LYM cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.
Journal of Vision, 2005
We propose a new luminosity function, V Ã ð1Þ, that improves upon the original CIE 1924 Vð1Þ func... more We propose a new luminosity function, V Ã ð1Þ, that improves upon the original CIE 1924 Vð1Þ function and its modification by D. and J. J. , while being consistent with a linear combination of the A. Stockman & L. T. Sharpe long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone fundamentals. It is based on experimentally determined 25 Hz, 2-diameter, heterochromatic (minimum) flicker photometric data obtained from 40 observers (35 males, 5 females) of known genotype, 22 with the serine variant L(ser180), 16 with the alanine L(ala180) variant, and 2 with both variants of the L-cone photopigment. The matches, from 425 to 675 nm in 5-nm steps, were made on a 3 log troland xenon white (correlated color temperature of 5586 K but tritanopically metameric with CIE D 65 standard daylight for the Stockman and Sharpe L-and M-cone fundamentals in quantal units) adapting field of 16-angular subtense, relative to a 560-nm standard. Both the reference standard and test lights were kept near flicker threshold so that, in the region of the targets, the total retinal illuminance averaged 3.19 log trolands. The advantages of the new function are as follows: it forms a consistent set with the new proposed CIE cone fundamentals (which are the Stockman & Sharpe 2000 cone fundamentals); it is based solely on flicker photometry, which is the standard method for defining luminance; it corresponds to a central 2-viewing field, for which the basic laws of brightness matching are valid for flicker photometry; its composition of the serine/alanine L-cone pigment polymorphism (58:42) closely matches the reported incidence in the normal population (56:44; Stockman & Sharpe, 1999); and it specifies luminance for a reproducible, standard daylight condition. V Ã ð1Þ is defined as 1:55Lð1Þ þ Mð1Þ, where Lð1Þ and Mð1Þ are the Stockman & Sharpe L-& M-cone (quantal) fundamentals. It is extrapolated to wavelengths shorter than 425 nm and longer than 675 nm using the Stockman & Sharpe cone fundamentals.
Graefes Archive for Clinical and Experimental Ophthalmology, 2006
Purpose To study the electroretinographic signals originating in the long-wavelength-sensitive (L... more Purpose To study the electroretinographic signals originating in the long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone pathways by means of large-field and multifocal cone type-specific electroretinograms (ERGs) in a patient with progressive cone dystrophy. Methods A 65-year-old male patient with colour vision disturbances (age at onset 10 years), loss of visual acuity (14 years), and central visual field defects (40 years) was investigated. Large-field flicker-ERG responses to stimuli that exclusively modulated the L-cones or the M-cones, or the two simultaneously (both in-phase and in counter-phase), were measured. Short-wavelength-sensitive (S) cones were not modulated. Multifocal ERGs (mfERGs) were also recorded, with a pattern-reversing display that modulated only the L- or the M-cones at equal cone contrasts and average quantal catches. Genetic analysis of L- and M-pigment genes was performed on genomic DNA isolated from peripheral venous blood. Results The patient showed a normal rod-driven ERG but reduced cone-driven electroretinographic amplitudes with normal implicit times in the International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERG. The large-field flicker-ERG responses to pure L-cone modulation were significantly above noise level but were substantially reduced in comparison with both normal trichromatic subjects and (otherwise normal) deuteranopes. The L-cone driven electroretinographic implicit times and phases were within normal limits. The M-cone driven electroretinographic responses were not detectable. A model fit of all the L- and M-cone driven flicker-ERG data revealed that the responses were exclusively driven by the L-cones. Consistently, the cone type-specific mfERGs showed severely reduced but detectable responses to L-cone-isolating stimuli. The M-cone driven multifocal-ERG responses were undistinguishable from noise. The L- and M-pigment gene array consisted of only a single L-pigment gene. The complete coding sequence of this gene was determined and showed no abnormality. Conclusions This patient exhibits a coincidence of progressive cone dystrophy and deuteranopia. The molecular genetic data of the L/M-pigment gene array is consistent with the deutan phenotype. It cannot be excluded that the rearrangement of the X-chromosome pigment gene array is responsible for the cone dystrophy in this patient. It is, however, suggested that the dichromacy and the cone dystrophy have different and independent genetic origins.
Vision Research, 2003
Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal wh... more Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In ''flecked retina diseases'' heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance.
PURPOSE. Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized... more PURPOSE. Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior results. METHODS. Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. RESULTS. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS. The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.
Nature Genetics, 1998
Total colourblindness (OMIM 216900), also referred to as rod monochromacy (RM) or complete achrom... more 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.
Investigative Ophthalmology & Visual Science, 2008
Journal of Vision, 2002
Multifocal visual evoked potentials (mfVEP) were recorded with a pattern-reversing display that m... more Multifocal visual evoked potentials (mfVEP) were recorded with a pattern-reversing display that modulated only the long wavelength-sensitive (L) cones or only the middle wavelength-sensitive (M) cones. Outside the central 5.8° (radius), the ratio of the amplitudes of the mfVEP responses to L-and M-cone modulation varied across the six subjects, ranging from 1.1 to 1.7. The responses from the central 1° (radius) showed a substantially lower ratio, ranging from 0.8 to 1.1 (average of 0.9). The variation among individuals outside the central fovea is probably due to differences in the ratio of the L/M cone input to both magno-and parvocellular pathways. The substantially lower ratios for the central responses is consistent with an L/M cone ratio closer to 1.0 in the central 1° and/or an adjustment in the gain of the L-versus M-cone contributions to the central parvocellular pathways. Taking into consideration evidence from other techniques, we believe it is unlikely that most individuals have a L/M cone ratio of 1.0 in the fovea. Instead, it appears that there is a change in gain before the mfVEP is generated in area 17.
Nature Neuroscience, 2002
We describe a compelling demonstration of large-scale developmental reorganization in the human v... more We describe a compelling demonstration of large-scale developmental reorganization in the human visual pathways. The developmental reorganization was observed in rod monochromats, a rare group of congenitally colorblind individuals who virtually lack cone photoreceptor function. Normal controls had a cortical region, spanning several square centimeters, that responded to signals initiated in the all-cone foveola but was inactive under rod viewing conditions; in rod monochromats this cortical region responded powerfully to rod-initiated signals. The measurements trace a causal pathway that begins with a genetic anomaly that directly influences sensory cells and ultimately results in a substantial central reorganization.
Documenta Ophthalmologica, 2006
The relative number of L- and M-cones varies greatly between individuals. Differences in the rela... more The relative number of L- and M-cones varies greatly between individuals. Differences in the relative number of L- and M-cones may also contribute to the sex difference in the ERG response amplitude reported several times. We therefore investigated the relative number of L- and M-cones and its impact on sex differences in ERG amplitudes. Multifocal ERG (mfERG) and multifocal oscillatory potentials (mfOP) combined with a cone silent substitution technique were used to investigate outer and inner retinal signals recorded from 7 female and 7 male trichromats. L:M ratios were estimated from peak amplitude as well as from area under curve (AUC) analysis. For mfERGs the L:M ratios estimates were independent of the method of analysis, while for mfOPs, differences were found which are possibly due to an artefact in the calculation of ratios for small responses. There was a tendency for lower L:M ratios in female than in male subjects for both analysis of mfERG and mfOP responses. The (L+M)-response amplitudes at both sites were slightly higher and the L:M ratios were lower for female than for male observers. Because the magnitude of the ERG amplitude differences is larger than could be explained by L:M-ratio and axial length differences, we conclude that it may be due to a direct effect of sex hormones on ion channel function.
Graefes Archive for Clinical and Experimental Ophthalmology, 2005
Background The Nagel anomaloscope Model I is the definitive clinical instrument for classifying p... more Background The Nagel anomaloscope Model I is the definitive clinical instrument for classifying phenotypic variations in X-linked color-vision disorders. Its system of classification is based on the Rayleigh equation: the relative amounts of red and green primary lights required to match a yellow primary. Our aim was to characterize how changes in mains voltage and ambient temperature influence the wavelength and intensity of each primary and alter the Rayleigh matches of normal and anomalous trichromats. Methods A Nagel Model I anomaloscope was calibrated in wavelength and intensity while varying the temperature of its prism housing and the mains voltage. Three normal, three protanomalous and three deuteranomalous trichromats made Rayleigh matches at various temperatures and voltages. Results The intensities of the green and red primaries show an exponential growth with mains voltage. Additionally, the wavelengths and intensities of all three primaries change with prism housing temperature. As a result, the R-G match midpoints of normal and anomalous trichromats shift with increasing mains voltage, and more markedly with increasing prism housing temperature, to higher R-G settings. Conclusions Rayleigh matches obtained with the Nagel I anomaloscope are sensitive to changes in voltage supply and prism housing temperature, arising largely from thermal effects of the internal light sources. However, the instrument may still be safely used for diagnostic and research purposes provided that: (1) a stable voltage supply is used; (2) it is kept at a constant temperature; and (3) the match midpoint of the reference population has been established under identical conditions.
Vision Research, 1999
Using heterochromatic flicker photometry, we have measured the corneal spectral sensitivities of ... more Using heterochromatic flicker photometry, we have measured the corneal spectral sensitivities of the X-chromosome-linked photopigments in 40 dichromats, 37 of whom have a single opsin gene in their tandem array. The photopigments encoded by their genes include: the alanine variant of the normal middle-wavelength sensitive photopigment, M(A180); the alanine and serine variants of the normal long-wavelength sensitive photopigment, L(A180) and L(S180); four different L -M hybrid or anomalous photopigments, L2M3(A180), L3M4(S180), L4M5(A180) and L4M5(S180); and two variants of the L-cone photopigment, encoded by genes with embedded M-cone exon two sequences, L(M2; A180) and L(M2; S180). The peak absorbances (u max ) of the underlying photopigment spectra associated with each genotype were estimated by correcting the corneal spectral sensitivities back to the retinal level, after removing the effects of the macular and lens pigments and fitting a template of fixed shape to the dilute photopigment spectrum. Details of the genotype-phenotype correlations are summarized elsewhere (Sharpe, L. T., Stockman, A., Jägle, H., Knau, H., Klausen, G., Reitner, A. et al. (1998). J. Neuroscience, 18, 10053 -10069). Here, we present the individual corneal spectral sensitivities for the first time as well as details and a comparison of three analyses used to estimate the u max values, including one in which the lens and macular pigment densities of each observer were individually measured.
American Journal of Ophthalmology, 2004
PURPOSE: To investigate short-term visual effects of a single 100-mg dose of Viagra (sildenafil c... more PURPOSE: To investigate short-term visual effects of a single 100-mg dose of Viagra (sildenafil citrate) in healthy men.