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PubMed2000

Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

ATP-Binding Cassette Transporters↗

PubMed2001

The destabilization of human GCAP1 by a proline to leucine mutation might cause cone-rod dystrophy.

Guanylate cyclase activating protein-1 (GCAP1) is required for activation of retinal guanylate cyclase-1 (RetGC1), which is essential for recovery of photoreceptor cells to the dark state. In this paper, experimentally derived observations are reported that help in explaining why a proline-->leucine mutation at position 50 of human GCAP1 results in cone-rod dystrophy in a family carrying this mutation. The primary amino acid sequence of wild-type GCAP1 was mutated using site-directed mutagenesis to give a leucine at position 50. In addition, serine replaced a glutamic acid residue at position 6 to promote N-terminal myristoylation, yielding the construct GCAP1 E6S/P50L. The enzyme was over-expressed in Escherichia coli cells, isolated and purified before being used in assays with RetGC1, characterized by circular dichroism (CD) spectroscopy, and investigated for protease resistance and thermal stability. Assays of cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate by RetGC1 in the presence of E6S/P50L showed that E6S/P50L could activate RetGC1 and displayed similar calcium sensitivity to wild-type GCAP1. In addition, E6S/P50L and wild-type GCAP1 possess similar CD spectra. However, there was a marked increase in the susceptibility to protease degradation and also a reduction in the thermal stability of E6S/P50L as observed by both the cGMP assay and CD spectroscopy. It is therefore suggested that although GCAP1 E6S/P50L has a similar activity and calcium dependency profile to the wild-type GCAP1, its lower stability could reduce its cellular concentration, which would in turn alter [Ca2+] and result in death of cells.

Amino Acid Sequence↗

PubMed2004

Full-field ERG responses recorded with skin electrodes in paediatric patients with retinal dystrophy.

PURPOSE: Assess ERG responses recorded with skin electrodes in children with retinal dystrophies. METHOD: ERG responses were recorded using skin electrodes in 17 healthy children and 43 paediatric patients with retinal dystrophy. Subjects were aged 4-14 years. ERG responses were recorded to full-field stimuli similar to those recommended in the ISCEV standard. The type of retinal dystrophy was classified on the basis of standard clinical criteria and the ERG responses were compared with those of the age-matched controls. RESULTS: ERG responses were abnormal in every patient. The specific type of ERG abnormality was also consistent with the clinical findings in the majority of patients. Rod responses were abnormal in every patient with a rod-cone dystrophy and cone responses were also abnormal in the majority of patients. Those patients with cone dystrophy or rod monochromatism had normal or near normal rod responses but sub-normal or absent cone responses. Patients with CSNB or XLRS had a sub-normal b-wave but normal amplitude a-wave. CONCLUSION: ERGs can be recorded successfully with skin electrodes in paediatric patientsand responses can aid the diagnosis of the type of retinal dystrophy.

Adolescent↗

PubMed1997

Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor.

Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A). In another CRD family, a 1 bp deletion (E168 [delta1 bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptors.

Adult↗

PubMed1999

Distribution of pigment epithelium autofluorescence in retinal disease state recorded in vivo and its change over time.

BACKGROUND: Recently a technique of imaging the retinal pigment epithelium (RPE) has been developed that takes advantages of its intrinsic fluorescence derived from lipofuscin. The purpose of this study was to document the distribution of fundus autofluorescence in patients with various retinal diseases and its change over time. METHODS: The intensity and spatial distribution of fundus autofluorescence was documented in 318 eyes from 159 patients with various retinal diseases using a confocal Laser Scanning Ophthalmoscope. Thirty patients with macular dystrophies and 30 with age-related macular disease underwent serial examinations over a period of 1-3 years in order to monitor the changes over time of fundus autofluorescence. RESULTS: Absent autofluorescence corresponded well spatially with outer retinal atrophy in eyes with retinitis pigmentosa and rod-cone dystrophy. Abnormally high background autofluorescence was seen in the macular region in some patients with dominant and recessive retinitis pigmentosa and rod-cone dystrophies. In areas of macular edema fundus autofluorescence was abnormal. Fundus autofluorescence showed changes over time in most of the eyes with retinal diseases studied. CONCLUSION: Fundus autofluorescence allows documentation of areas of photoreceptor cell loss in eyes with retinitis pigmentosa and rod-cone dystrophies. If abnormal high background autofluorescence in the surviving areas occurs only in some patients with retinitis pigmentosa, the technique may serve to distinguish the regional from the diffuse type of disease. Over time, fundus autofluorescence may demonstrate change or may remain stable.

Adolescent↗

PubMed2002

Keratoconus associated with cone-rod dystrophy: a case report.

A 31-year-old man with bilateral keratoconus associated with apical corneal scarring underwent uneventful penetrating keratoplasty in his left eye. Postoperatively his best-corrected visual acuity did not improve beyond 20/120. Examination of the fundus revealed features suggestive of bull's eye maculopathy. On performing an electroretinogram study of both eyes, grossly delayed implicit time with reduced amplitudes of the rod response and extinguished cone waveforms were noted, indicating cone-rod dystrophy. Color blindness was also noted on testing with Ishihara's pseudoisochromatic plates. Genetic counseling showed this to be an isolated defect with negative family history. Preoperative electrophysiologic studies may have a prognostic role in these cases.

Adult↗

PubMed2000

HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model.

PURPOSE: To investigate the function and pathogenicity of HRG4, a photoreceptor synaptic protein homologous to the Caenorhabditis elegans neuroprotein UNC119. METHODS: HRG4 was screened for mutations in patients with various retinopathies, and a transgenic mouse model was constructed and analyzed based on a mutation found. RESULTS: A heterozygous premature termination codon mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy. In some transgenic mice carrying the identical mutation, age-dependent fundus lesions developed accompanied by electroretinographic changes consistent with defects in photoreceptor synaptic transmission (depressed b-wave, normal c-wave), and retinal degeneration occurred with marked synaptic and possible transsynaptic degeneration. CONCLUSIONS: HRG4, the only synaptic protein known to be highly enriched in photoreceptor ribbon synapses, is now shown to be pathogenic when mutated.

Adaptor Proteins, Signal Transducing↗

PubMed1998

A new family of Greek origin maps to the CRD locus for autosomal dominant cone-rod dystrophy on 19q.

Retinal photoreceptor dystrophies (RD) are a highly heterogeneous group of genetic disorders of the retina, representing the most frequently inherited form of visual handicap, affecting approximately 1.5 million people world wide. To date, more than 40 genetic loci have been implicated in RD. One of them, the CORD2 locus, for an autosomal dominant form of cone-rod dystrophy (CRD), maps to chromosome 19q and has previously been reported in a single large family of British origin. We now report a new family with severe early onset CRD, phenotypically very similar to the British family, which also maps to 19q, but is of Greek origin. Haplotype data of the Greek family showed no recombination between and including markers D19S219 and D19S246 and linkage analysis gave a lod score of 2.7 (at theta=0) with marker D19S412, confirming the data obtained in the British family.

Chromosome Mapping↗

PubMed2004

The R172W mutation in peripherin/rds causes a cone-rod dystrophy in transgenic mice.

Peripherin/rds (P/rds) is a membrane glycoprotein essential for the photoreceptor outer segment disc morphogenesis and maintenance. More than half of the disease-causing mutations in P/rds have been linked to different forms of macular dystrophy; the most common one is substitution of tryptophan for arginine at position 172 (R172W). Here we confirm the patient phenotype associated with the expression of R172W mutation in transgenic mice. Functional, structural and biochemical analyses showed that, while R172W P/rds is appropriately localized, a direct correlation exists between transgene expression levels and the onset/severity of the phenotype. In the wild-type background, both cone and rod photoreceptors' structure and function were significantly diminished, which indicates a dominant-negative, cone-rod defect. Whereas rds(+/-) mice maintained the normal cone function at early ages, cone responses in R172W/rds(+/-) mice were diminished to 41% of the wild-type level signifying a preferential damaging effect of the mutation on cones. Conversely, R172W/rds(+/-) mice showed a significant rescue of rod function and improvement of rod outer segment structure. Although rds(-/-) mice have no detectable rod or cone responses, R172W/rds(-/-) animals retained 30% of wild-type structure and rod function, but no significant rescue of cone function was detected at 1 month of age. No biochemical abnormalities were observed in complex formation and association with Rom-1; however, R172W protein was more sensitive to tryptic digestion, indicative of a change in protein conformation, possibly contributing to the cone-dominated phenotype. As the first animal model for P/rds-associated cone-rod dystrophy, R172W mice provide a valuable tool for studying the pathophysiology of P/rds-associated human retinal dystrophies and the development of therapeutic strategies to intervene in these diseases.

Animals↗

PubMed1999

Mutations in the rod outer segment membrane guanylate cyclase in a cone-rod dystrophy cause defects in calcium signaling.

Rod outer segment guanylate cyclase 1 (ROS-GC1) is a member of the subfamily of Ca(2+)-regulated membrane guanylate cyclases; and it is pivotal for vertebrate phototransduction. Two opposing regulatory modes control the activity of ROS-GC1. At nanomolar concentrations of Ca(2+), ROS-GC1 is activated by Ca(2+)-binding proteins named guanylate cyclase activating proteins (GCAPs). However, at micromolar concentrations of Ca(2+), ROS-GC1 is stimulated by S100beta [also named calcium-dependent (CD) GCAP]. This mode is not linked with phototransduction; instead, it is predicted to be involved in retinal synaptic activity. Two point mutations, E786D and R787C, in ROS-GC1 have been connected with cone-rod dystrophy (CORD6), with only one type of point mutation occurring in each family. The present study shows that the E786D mutation has no effect on the basal catalytic activity of ROS-GC1 and on its activation by GCAP1 and S100beta; however, the mutated cyclase becomes more activated by GCAP2. The R787C mutation has three consequences: (1) it causes major damage to the basal cyclase activity, (2) it makes the cyclase 5-fold more sensitive to activation by GCAP1; and 3) converts the cyclase into a form that is less sensitive to activation by GCAP2 and S100beta. Thus, the two CORD6-linked mutations in ROS-GC1, which occur at adjacent positions, result in vastly different biochemical phenotypes, and they are connected with very specific molecular defects in the Ca(2+) switching components of the cyclase. These defects, in turn, are proposed to have a profound effect on both the machinery of phototransduction and the retinal synapse. The study for the first time defines the biochemistry of CORD6 pathology in precise molecular terms.

Animals↗

PubMed2000

Impairment of the rod outer segment membrane guanylate cyclase dimerization in a cone-rod dystrophy results in defective calcium signaling.

Rod outer segment membrane guanylate cyclase1 (ROS-GC1) is the original member of the membrane guanylate cyclase subfamily whose distinctive feature is that it transduces diverse intracellularly generated Ca(2+) signals in the sensory neurons. In the vertebrate retinal neurons, ROS-GC1 is pivotal for the operations of phototransduction and, most likely, of the synaptic activity. The phototransduction- and the synapse-linked domains are separate, and they are located in the intracellular region of ROS-GC1. These domains sense Ca(2+) signals via Ca(2+)-binding proteins. These proteins are ROS-GC activating proteins, GCAPs. GCAPs control ROS-GC1 activity through two opposing regulatory modes. In one mode, at nanomolar concentrations of Ca(2+), the GCAPs activate the cyclase and as the Ca(2+) concentrations rise, the cyclase is progressively inhibited. This mode operates in phototransduction via two GCAPs: 1 and 2. The second mode occurs at micromolar concentrations of Ca(2+) via S100beta. Here, the rise of Ca(2+) concentrations progressively stimulates the enzyme. This mode is linked with the retinal synaptic activity. In both modes, the final step in Ca(2+) signal transduction involves ROS-GC dimerization, which causes the cyclase activation. The identity of the dimerization domain is not known. A heterozygous, triple mutation -E786D, R787C, T788M- in ROS-GC1 has been connected with autosomal cone-rod dystrophy in a British family. The present study shows the biochemical consequences of this mutation on the phototransduction- and the synapse-linked components of the cyclase. (1) It severely damages the intrinsic cyclase activity. (2) It significantly raises the GCAP1- and GCAP2-dependent maximal velocity of the cyclase, but this compensation, however, is not sufficient to override the basal cyclase activity. (3) It converts the cyclase into a form that only marginally responds to S100beta. The mutant produces insufficient amounts of the cyclic GMP needed to drive the machinery of phototransduction and of the retinal synapse at an optimum level. The underlying cause of the breakdown of both types of machinery is that, in contrast to the native ROS-GC1, the mutant cyclase is unable to change from its monomeric to the dimeric form, the form required for the functional integrity of the enzyme. The study defines the CORD in molecular terms, at a most basic level identifies a region that is critical in its dimer formation, and, thus, discloses a single unifying mechanistic theme underlying the complex pathology of the disease.

Amino Acid Substitution↗

PubMed2004

Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.

OBJECTIVE: To investigate the clinical spectrum and molecular causes of retinal dystrophies in 3 families. DESIGN: Family molecular genetics study. PARTICIPANTS: Sixteen patients and 15 relatives in 3 families. METHODS: Members of 3 families with multiple ABCA4-associated retinal disorders were clinically evaluated. Deoxyribonucleic acid samples of all affected individuals and their family members were analyzed for variants in all 50 exons of the ABCA4 gene. MAIN OUTCOME MEASURES: ABCA4-associated retinal phenotypes and mutations in the ABCA4 gene. RESULTS: In family A, 2 sisters were diagnosed with Stargardt's disease (STGD); the eldest sister was compound heterozygous for the mild 2588G-->C and the severe 768G-->T mutation. Another patient in this family with a severe type of retinitis pigmentosa (RP) carried the 768G-->T mutation homozygously. In family B, 2 siblings presented with an RP of severity similar to that encountered in family A. Both were homozygous for the severe IVS33+1G-->A mutation. Two other family members with STGD were compound heterozygous for the 2588G-->C and IVS33+1G-->A mutations. In family C, all 5 siblings of generation II demonstrated age-related macular degeneration (AMD). In generations III and IV, 2 STGD patients and 1 cone-rod dystrophy (CRD) patient were present. In 1 STGD patient we identified a heterozygous 768G-->T mutation. Sequence analysis of the entire ABCA4 gene did not reveal the remaining 2 mutations. Nevertheless, the 2 patients with STGD, the patient with CRD, and 2 of the AMD patients shared a common haplotype spanning the ABCA4 gene. CONCLUSIONS: Different mutations in the ABCA4 gene are the cause of STGD and RP or CRD in at least 2 and, possibly, 3 families. Patients with RP caused by ABCA4 mutations are characterized by an early onset and rapid progression of their retinal dystrophy, with extensive chorioretinal atrophy resulting in a very low visual acuity. Various combinations of relatively rare retinal disorders such as STGD, CRD, and RP in one family may not be as uncommon as once believed, in view of the relatively high carrier frequency of ABCA4 mutations (about 5%) in the general population.

ATP-Binding Cassette Transporters↗

PubMed2005

Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene.

PURPOSE: To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 5-generation family, and to examine the phenotype and degree of intrafamilial variability. DESIGN: Family genetic study. PARTICIPANTS: Nine affected individuals from a nonconsanguineous British family. METHODS: Ophthalmologic examination, color vision testing, fundus photography, autofluorescence imaging, and electrophysiological assessment were performed. The clinical notes of 2 additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed, and subsequent mutation screening of the peripherin/RDS gene. RESULTS: Linkage analysis established a disease interval on chromosome 6p, which harbored the retinal candidate gene, peripherin/RDS. The 3 coding exons of the peripherin/RDS gene were subsequently screened for mutations in affected and unaffected family members. A nonconservative missense substitution, Arg172Trp (R172W), segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and color vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern electroretinograms (ERGs) consistent with macular dysfunction and 4 subjects showed additional full-field ERG abnormalities, providing evidence of generalized retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation, ranging from severe cone-rod dystrophy to asymptomatic individuals with normal retinal function. CONCLUSIONS: The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intrafamilial and interfamilial consistency of phenotype. This is the first report describing marked intrafamilial variation associated with this mutation, including nonpenetrance. These findings are clinically important in relation to advice on prognosis and accurate genetic counseling.

Adolescent↗

PubMedDate not supplied

Optic disc pallor: a false localizing sign.

A 20-year-old pregnant woman was referred with bilateral mild visual acuity loss and optic disc pallor. Because of profound color vision deficits out of proportion to her acuity loss, an abnormality of the cone photoreceptors was suspected. An electroretinogram confirmed the diagnosis of a cone dystrophy and precluded further costly and invasive testing. Cone dystrophy should be considered in the differential diagnosis of any patient with bilateral, nonrefractive visual loss, especially if color vision is disproportionately affected, even with a normal retinal appearance and no significant family history.

Adult↗

PubMed1998

ABCR unites what ophthalmologists divide(s)

Over the last years, the molecular causes of monogenic chorioretinal diseases have been elucidated at an increasing pace. In contrast, only recently have genetic factors been found that contribute to multifactorial eye disorders such as age-related macular degeneration (AMD). Mutations in the retina-specific ATP-binding cassette transporter gene (ABCR) cause recessive Stargardt's disease (STGD) and fundus flavimaculatus (FFM), and were also found in 16% of patients with AMD. In addition, ABCR mutations were identified in families with recessive retinitis pigmentosa (RP), cone dystrophy (COD), and cone-rod dystrophy (CRD). In this review, we summarize these findings and propose a model which provides a framework to explain the observed genotypes and phenotypes. We hypothesize that most ABCR mutations can be classified in different classes of severity, and that, depending on the remaining total activity of ABCR, the phenotype can range from AMD at the mild end to RP at the severe end of the spectrum. This model allows us to make several predictions on the type and/or severity of ABCR mutations that are present in patients with AMD, STGD/FFM, COD, CRD, and RP.

ATP-Binding Cassette Transporters↗

PubMed1998

Cone-rod dystrophy with serpentine-like retinal deposits.

OBJECTIVE: To describe the clinical and electrophysiologic findings in a novel retinal dystrophy. METHODS: Ophthalmologic and electrophysiologic examinations were performed in 3 affected members of 1 family: a 10-year-old girl, her 30-year-old mother, and her 59-year-old maternal grandfather. Electro-oculography (EOG) and electroretinography (ERG) were performed according to the standards of the International Society for Clinical Electrophysiology of Vision. RESULTS: In all 3 family members, gray, serpentine-like deposits were seen at the level of the retinal pigment epithelium (RPE). These were most distinct in the child, less prominent in her mother, and barely visible in the grandfather. Visual acuity was 20/25 OU in the child and 20/200 OU in both adults. Visual field testing showed normal outer limits and small paracentral scotomas in both adults. Electroretinographic recording revealed slightly reduced amplitudes in the 10-year-old girl, cone dysfunction in her mother, and cone-rod dysfunction in the grandfather. Multifocal ERG responses were reduced but recordable in the mother. The EOG light peak amplitude was normal in both females and borderline in the grandfather. The light peak was delayed in all 3 patients. CONCLUSIONS: Similar deposits at the level of the RPE have not been described in other inherited retinal dystrophies. This family appears to have a novel form of cone-rod dystrophy with deposits at the level of the RPE and probable autosomal dominant inheritance.

Adult↗

PubMed1992

Fundus flavimaculatus with severely reduced cone electroretinogram.

An 11-year-old girl complaining of progressive visual loss in both eyes showed atrophic macular degeneration with yellowish white flecks around the fovea in both eyegrounds. Decreased vision, central scotoma with normal peripheral visual field, and angiographic dark choroid except for transmitted hyperfluorescence in the macula and at the flecks confirmed the diagnosis of fundus flavimaculatus with atrophic macula. Electroretinograms, however, revealed severely reduced cone responses associated with almost normal rod response, which led to the diagnosis of cone dystrophy. The rare combination of angiographic evidence of fundus flavimaculatus and electroretinographically diagnosed cone dystrophy was discussed.

Child↗

PubMed2002

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. RESULTS: In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. CONCLUSIONS: Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

ATP-Binding Cassette Transporters↗