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Results for “Cone dystrophy”

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At least 289 records · Page 16Linked to original sources

PubMed2005

Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels.

PURPOSE: To characterize the functional consequences of disease-associated mutations in the CNGB3 (B3) subunit of human cone photoreceptor cyclic nucleotide-gated channels in order to gain insight into disease mechanisms. METHODS: Three separate disease-associated mutations were generated in CNGB3: F525N, R403Q, and T383fsX. These mutant subunits were then heterologously expressed in Xenopus oocytes in combination with wild type CNGA3 (A3) subunits, and characterized by patch-clamp recording in the inside-out configuration. RESULTS: Co-expression of A3 and B3F525N, A3 and B3R403Q, or A3 and B3R403Q and B3T383fsX subunits resulted in channels that exhibited an increase in ligand sensitivity without a reduction in current density compared to wild-type heteromeric channels. Each simulated disease state produced channels that exhibited greater sensitivity to block by L-cis-diltiazem than homomeric CNGA3 channels, confirming that the mutant CNGB3 subunits were competent to form functional heteromeric channels. Each combination of subunits displayed an increase in apparent affinity for cGMP relative to wild-type heteromeric channels. However, F525N enhanced cGMP apparent affinity to a significantly greater extent than the other two modeled disease states. CONCLUSIONS: We have examined the gating effects of two previously uncharacterized disease-associated mutations in the CNGB3 subunit and found that in each case, the mutations resulted in a gain of function molecular phenotype. Furthermore, the magnitude of the effect on channel function correlated with the severity of the associated disease. The complete achromatopsia-associated F525N mutation resulted in more pronounced alterations in channel function than the mutation combinations linked to macular degeneration or progressive cone dystrophy.

Animals↗

PubMed1995

Photoaversion in Leber's congenital amaurosis.

Photoaversion is a prominent symptom of a number of infantile genetic ocular disorder such as congenital glaucoma, aniridia, albinism, and cone dystrophies including achromatopsia. Photoaversion has not been widely recognized as a clinical feature of Leber's congenital amaurosis. We present two patients who were diagnosed clinically with achromatopsia because of nystagmus, absent color vision, reduced visual acuity, and moderately severe photoaversion in the absence of anterior segment abnormalities. The photopic and scotopic responses of the electroretinogram (E R G) were nonrecordable in both patients indicating involvement of both cone and rod systems. The diagnosis was then revised to one of Leber's congenital amaurosis. Photoaversion can be a prominent clinical feature in some patients with Leber's congenital amaurosis. The E R G clinches the diagnosis. These patients may constitute a distinct genetic subtype of the disease and molecular genetic studies will help resolve this issue.

Blindness↗

PubMed2007

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling.

X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6-20%; RPGR: 78.4% vs. 55-90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.

Child↗

PubMed2004

[Clinical and genetic findings in a patient with fundus albipunctatus].

METHODS: The 38-year-old index patient was examined by visual acuity testing, perimetry, dark adaptometry, funduscopy, electroretinogram (ERG), and multifocal ERG. She was screened for mutations in exons 2-5 and exon/intron boundaries of the 11- cis retinol dehydrogenase gene by direct sequencing. RESULTS: Visual acuity was 1.0, but perimetry revealed paracentral scotomas associated with reading problems. The optic discs were normal. After 45 min of darkness there was nearly no increase of light sensitivity. After 30 min of dark adaptation, the scotopic ERG showed reduced amplitudes, but after 60 min a nearly normal level was reached. The 30-Hz flicker response of the cone ERG showed borderline implicit times, but no reduction of amplitudes. However, multifocal ERG clearly disclosed a paracentral amplitude reduction as the reason for the visual field defects. The fundus was typical for fundus albipunctatus. The patient is a compound heterozygote carrying a Ile33Asn and a Arg157Trp mutation. CONCLUSIONS: The paracentral visual field defects were due to cone dysfunction. So far the patient exhibits no cone dystrophy.

Adult↗

PubMed2003

Identification and light-dependent translocation of a cone-specific antigen, cone arrestin, recognized by monoclonal antibody 7G6.

PURPOSE: To elucidate the antigen recognized by monoclonal antibody (mAb) 7G6, a widely used cone-specific marker. METHODS: 7G6 immunocytochemistry was performed on sections of human, primate, and bovine retina. The antigen was immunoprecipitated from human retinal lysates and purified with protein G. Edman degradation and liquid chromatography of tryptic peptides combined with tandem mass spectrometry (LC-MS/MS) identified the antigen. RESULTS: Sequencing of peptides derived from the immunoprecipitated 7G6 antigen identified it as cone arrestin. The identity was confirmed by Western blot analysis with recombinant human cone arrestin and competition with the antibody in immunocytochemistry. Subcellular localization of cone arrestin in dark-adapted and bleached bovine retinas showed that cone arrestin accumulated in cone outer segments of light-adapted retina but was more concentrated in the inner segments of dark-adapted retina. By expression of truncated human cone arrestin mutants systematically deleting areas divergent from bovine and primate cone arrestins, the epitope of 7G6 was identified as a divergent loop exposed at the surface within the N-domain of cone arrestin. CONCLUSIONS: Several independent methods established that the 7G6 antigen is cone arrestin. The 7G6 epitope is contained in a divergent loop, the sequence of which is conserved in bovine and primates but not other vertebrate species consistent with the specificity of the antibody. The light-dependent translocation of cone arrestin suggests a role in light-dark adaptation of cones. Because of the location of its gene on the X-chromosome, cone arrestin is a candidate gene for X-linked cone dystrophies.

Amino Acid Sequence↗

PubMed1998

A comparison of the optical Stiles-Crawford effect and retinal densitometry in a clinical setting.

PURPOSE: To compare the measurement of the optical Stiles-Crawford effect (SCE) to the densitometry of cone visual pigments in a clinical setting. Both tests provide information on outer retinal integrity, but the optical SCE can be performed in far less time. METHODS: Images acquired with a custom-built scanning laser ophthalmoscope were used to assess visual pigment density and optical SCE. Visual pigment density was regarded as the "gold standard." More than 100 patients with suspected, and some with known, outer retinal pathology were tested. The group included cases of central serous detachment, cone dystrophy, Stargardt's disease, Best's disease, and retinitis pigmentosa. RESULTS: Parameters of the optical SCE of 25 healthy subjects and 106 patients were taken through a stepwise linear regression to predict density. The correlation between predicted density from the optical SCE and the measured density was 0.82. The sensitivity of the optical SCE to detect decreased density was 96%. When only the foveal reflectance was considered, sensitivity was still 84% CONCLUSIONS: The optical SCE is a sensitive and fast method for detecting cone photoreceptor disturbances.

Adult↗

PubMedDate not supplied

Progressive human cone-rod dysfunction (dystrophy).

The author has classified progressive human cone-rod dysfunction into primary and secondary types. The primary type, identified by early ERG cone and usually also rod abnormalities, was further subdivided into types 1 and 2 based on, amoung other distinguishing characteristics, the extent of associated retinal pigment epithelial defects. Secondary cone-rod dysfunction apparently results from disease initially affecting the retinal pigment epithelium. Initially normal ERG findings and the presence of flecks characterize this (type 3) progressive cone-rod dysfunction.

Adolescent↗

PubMed2004

Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis.

Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia.

Alcohol Oxidoreductases↗

PubMed2000

Degeneration of cone photoreceptors induced by expression of the Mas1 protooncogene.

Although transgenic expression of oncogenes typically leads to tumorigenesis, oncogene expression directed to the rod photoreceptors leads to cell death without tumor formation. To evaluate the cellular and functional changes induced in cone photoreceptors by an oncogene, the Mas1 protooncogene was targeted to the cones of transgenic mice by the human red/green opsin promoter. Mas1 was chosen because of its exclusive expression in the nervous system and its homology to opsin. The overall histologic appearance of the transgenic retina was normal and retinal tumors were never observed. While rod-mediated electroretinograms were normal in all respects, cone-mediated responses were diminished in direct relationship to the level of transgene expression as determined by Northern blot analysis. Responses of UV- and green-sensitive cones were reduced equivalently, and Northern analysis and immunocytochemistry indicated that cone photoreceptor densities were markedly diminished throughout transgenic retinas. These results indicate that oncogene expression in cones induces cell death without tumor formation and support the possibility that aberrant oncogene expression may underlie some forms of hereditary retinal diseases. The Mas1 transgenic mice may be useful in understanding the cone photoreceptor degeneration that occurs in cone dystrophies and age-related macular degeneration and in evaluating potential therapies for these disorders.

Aging↗

PubMed1998

Evidence supportive of a functional discrimination between photopic oscillatory potentials as revealed with cone and rod mediated retinopathies.

We report on a family where four of the eleven children presented with reduced visual acuities, a red-green deficit at the Farnsworth-Munsel FM 100-hue test, normal appearing fundi and unexpected electroretinographic findings. Light- (photopic) and dark- (scotopic) adapted electroretinograms (ERG) and oscillatory potentials (OPs) were obtained following an accepted standard protocol. The b-wave of their photopic ERG was significantly more attenuated than the a-wave due to the specific abolition of OP4, while the amplitudes of OP2 and OP3 were within the normal range, giving to the b-wave a truncated appearance reminiscent of that seen in congenital stationary night blindness (CSNB) with myopia. Interestingly in the latter condition, which is believed to result from an ON-retinal pathway anomaly, it is OP2 and OP3 which are specifically abolished while OP4 is of normal amplitude thus resulting in an OP response pattern which complements that seen with our patients. Also of interest is the fact that, in our patients, the amplitude of the dark-adapted OP2 was, on average, 240% larger than that measured in light-adaptation while, in normal, a non-significant 14% increase is noted; a finding which is in keeping with other studies reporting supernormal scotopic ERGs in some forms of cone dystrophies. Based on the photopic OP response pattern, our patients represent the electrophysiological complement of patients affected with CSNB. Interestingly their symptoms are also complementary, a finding which could support a functional discrimination between the photopic OPs.

Adolescent↗

PubMed1998

Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration.

Photoreceptor membrane guanylate cyclases (RetGC) are regulated by calcium-binding proteins, GCAP-1 and GCAP-2. At Ca2+ concentrations below 100 nM, characteristic of light-adapted photoreceptors, guanylate cyclase-activating protein (GCAPs) activate RetGC, and at free Ca2+ concentrations above 500 nM, characteristic of dark-adapted photoreceptors, GCAPs inhibit RetGC. A mutation, Y99C, in human GCAP-1 was recently found to be linked to autosomal dominant cone dystrophy in a British family (Payne, A. M., Downes, S. M., Bessant, D. A. R., Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). We produced recombinant Y99C GCAP-1 mutant and tested its ability to activate RetGC in vitro at various free Ca2+ concentrations. The Y99C mutation does not decrease the ability of GCAP-1 to activate RetGC. However, RetGC stimulated by the Y99C GCAP-1 remains active even at Ca2+ concentration above 1 microM. Hence, the cyclase becomes constitutively active within the whole physiologically relevant range of free Ca2+ concentrations. We have also found that the Y99C GCAP-1 can activate RetGC even in the presence of Ca2+-loaded nonmutant GCAPs. This is consistent with the fact that cone degeneration was dominant in human patients who carried such mutation (Payne, A. M., Downes, S. M., Bessant, D. A. R. , Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). A similar mutation, Y104C, in GCAP-2 results in a different phenotype. This mutation apparently does not affect Ca2+ sensitivity of GCAP-2. Instead, the Y104C GCAP-2 stimulates RetGC less efficiently than the wild-type GCAP-2. Our data indicate that cone degeneration associated with the Y99C mutation in GCAP-1 can be a result of constitutive activation of cGMP synthesis.

Amino Acid Sequence↗

PubMed2001

Electroretinogram contact lens electrode with tri-color light-emitting diode.

PURPOSE: This study was performed to evaluate a new electroretinogram (ERG) contact lens electrode containing four light-emitting diodes (LEDs) that are used for both stimulus and background light. METHODS: The luminance of each LED could be changed independently and used as stimulus light. Red, blue, bright white, and flickering ERGs were recorded in 12 normal subjects and two patients with progressive cone dystrophy. The long-duration light stimuli separated the on- and off-responses of the ERG. This equipment is not according to the ISCEV standard. RESULTS: The tri-color LED electrode contact lens can efficiently produce and record ERG responses. Off-responses were recordable separately from on-responses by lengthening the stimulus duration. CONCLUSION: This combined stimulus-electrode system is compact and portable. Combined with the portable amplifier and the recorder, the ERGs can be recorded easily in an operating room, at patients' bedside, and in remote locations away from clinics and hospitals.

Adult↗

PubMedDate not supplied

The a-wave latency in control subjects and patients with retinal diseases.

PURPOSE: To determine the a-wave latency of the electroretinograms (ERGs) recorded from control subjects and patients with retinal diseases. METHODS: The a-wave latency and implicit time (IT) were measured retrospectively from the ERGs of 40 control subjects and 99 patients. The patients included 9 with complete congenital stationary night blindness (cCSNB), 13 with achromatopsia or cone dystrophy, 5 with supernormal and delayed rod ERG syndrome, and 72 with retinitis pigmentosa (RP). To assess whether latency measurements can be obtained reliably by different observers from patients with smaller a-wave amplitudes and noisier baselines, the a-wave latency and IT of the ERG of the right eye of 10 control subjects and 10 patients with RP were measured by three observers. RESULTS: The mean a-wave latency measured for the same 10 control ERGs by three observers differed by less than 1 millisecond while the mean IT differed by 1.7 milliseconds. For 10 ERGs from RP patients, the mean for the a-wave latency measured by the three observers differed by less than 2.0 milliseconds and by 1.1 millisecond for the IT. The coefficient of variation varied from 24.8% to 36.7% for the latency and from 11.5% to 16.0% for the IT. The a-wave latencies elicited by the 0-dB stimulus under scotopic and photopic conditions from the 40 control subjects were not statistically different. The a-wave latency in patients with cCSNB did not differ significantly from that in control subjects. The longer a-wave latency in patients with achromatopsia suggested that the rods have a longer latency than cones. The scotopic and photopic a-wave latencies were significantly longer in RP patients. The longer latency in RP patients was not due to smaller a- or b-wave amplitudes. CONCLUSIONS: The a-wave latency can be measured as reliably as the IT in control subjects but the reliability is not as good for the latency as for the IT in RP patients. The larger coefficients of variation in RP patients were most likely due to the measurements being made from RP patients at different stages of their disease. Our results suggest that the a-wave latency in control subjects is determined by cones under both scotopic and photopic conditions. The longer a-wave latency in RP patients suggests that the rods and cones are altered over a significant area of the retina.

Adolescent↗

PubMed1994

Postreceptoral contribution to macular dysfunction in retinitis pigmentosa.

PURPOSE: To understand the sites of macular dysfunction in retinitis pigmentosa by evaluating focal electroretinogram (FERG) fundamental and second harmonic components, which are dominated by the activity of the outer and inner retina, respectively. METHODS: FERGs were recorded in response to a uniform field (9 degrees x 9 degrees) flickered sinusoidally at either 8 Hz or 32 Hz. The fundamental components of the responses to both the 8-Hz and 32-Hz stimuli and the second harmonic of the response to the 8-Hz stimulus were measured in their amplitudes and phases. Normal subjects (n = 17), as well as patients with typical retinitis pigmentosa (n = 22), cone dystrophy (CD, n = 7) and X-linked congenital retinoschisis (XLR, n = 5) served as subjects. The fundamental (32-Hz)-second harmonic (8 Hz) amplitude ratio was taken as an index of the relative function of outer-inner layers of the macula. RESULTS: Compared to controls, patients with retinitis pigmentosa showed losses of both FERG fundamental and second harmonic and an increase of the fundamental-second harmonic ratio. Patients with CD also showed losses of both fundamental and second harmonic, but the fundamental-second harmonic ratio was normal. Patients with XLR had a selective loss of the second harmonic, resulting in an increased fundamental-second harmonic ratio. On average, the fundamental-second harmonic ratio of patients with retinitis pigmentosa tended to increase with age. CONCLUSIONS: The results suggest that in retinitis pigmentosa, both receptoral and postreceptoral sites contribute to macular dysfunction. This differs from CD and XLR, where losses appear more selective for the outer and the inner retina. Postreceptoral losses in retinitis pigmentosa may become larger with increasing age.

Adolescent↗

PubMed2001

CNGA3 mutations in hereditary cone photoreceptor disorders.

We recently showed that mutations in the CNGA3 gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated 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.

Amino Acid Sequence↗

PubMed2003

Imaging a child's fundus without dilation using a handheld confocal scanning laser ophthalmoscope.

Images of the fundus were acquired in children without pupil dilation using a prototype handheld confocal scanning laser ophthalmoscope (SLO). A 780-nm laser beam imaged a 20 degrees x 20 degrees area of the fundus while a 645-nm beam scanned a fixation target. Scorable images of the optic nerve, macula, and vessels were obtained in 67 (72%) of 93 eyes from pediatric patients with nystagmus, amblyopia, media opacities, or optic nerve or macular abnormalities. Images were obtained in all eyes of pediatric and adult controls. Unsuccessful imaging was associated with media opacities, high refractive error, and poor cooperation. Disadvantages of the SLO were the inability to detect optic nerve pallor or consistently image the periphery. Advantages of the SLO were seen in children with nystagmus, photophobia, eccentric fixation, cone dystrophy, and mild papilledema.

Adolescent↗

PubMed1991

Mizuo phenomenon in X-linked retinoschisis. Pathogenesis of the Mizuo phenomenon.

Four unrelated males with X-linked retinoschisis and a golden fundus reflex had Mizuo-Nakamura phenomenon, which, to our knowledge, has been described only in Oguchi's disease and X-linked cone dystrophy. These findings, together with experimental observations and data from the literature, led us to hypothesize that the Mizuo-Nakamura phenomenon is caused by an excess of extracellular potassium in the retina as a result of a decreased potassium scavenging capacity of retinal Müller cells.

Adult↗

PubMed2005

Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a genetically heterogeneous multisystem disorder that causes severe visual impairment. Retinitis pigmentosa (RP), hypogonadism, digit and renal anomalies, obesity, and a variable degree of mental retardation characterize the disorder. Eight different loci have been identified on 2q31(BBS5), 3p13 (BBS3), 4q27 (BBS7), 11q13 (BBS1), 14q32 (BBS8), 15q22.3 (BBS4), 16q21 (BBS2), and 20p12 (BBS6). The ocular manifestations of Bardet-Biedl syndrome include an early and severe rod-cone dystrophy causing legal blindness in the second decade. Features of systemic phenotypic variability were proposed to distinguish patients mapped to either the BBS2, BBS3, or BBS4 loci but no phenotype-genotype correlation has been established for the ocular phenotype. We studied the three original families used for the identification of BBS2, BBS3, and BBS4 loci to define the ocular phenotypes of patients (n = 34) and obligate carriers (n = 32) using clinical examination and electroretinography (ERG). RP was severe and early in all cases. Myopia was associated with BBS3 and BBS4, but not BBS2. One patient with Bardet-Biedl syndrome also had iris and chorioretinal colobomata, features suggestive of Biemond syndrome.

Adolescent↗