<i>ABCA4</i>-Associated Retinal Degenerations Spare Structure and Function of the Human Parapapillary Retina

Cideciyan, Artur V.; Świder, Małgorzata; Alemán, Tomás S.; Sumaroka, Alexander; Schwartz, Sharon; Roman, Marisa I.; Milam, Ann H.; Bennett, Jean; Stone, Edwin M.; Jacobson, Samuel G.

doi:10.1167/iovs.05-0805

Cited by 114 publications

(104 citation statements)

References 60 publications

(60 reference statements)

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“…44 Typically, the peripapillary area is spared in retinal degeneration caused by ABCA4 variants. 45 However, this must be addressed in future studies with larger cohorts.…”

Section: Discussionmentioning

confidence: 99%

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in theABCA4Gene

Fritsche

Fleckenstein

Fiebig

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS [+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS [+].METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS [-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS.We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project.CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD. (Invest Ophthalmol Vis Sci.

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“…44 Typically, the peripapillary area is spared in retinal degeneration caused by ABCA4 variants. 45 However, this must be addressed in future studies with larger cohorts.…”

Section: Discussionmentioning

confidence: 99%

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in theABCA4Gene

Fritsche

Fleckenstein

Fiebig

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Twelve patients were evaluated on multiple visits, while the remainder had single visits only. In our population of 129 patients with ABCA4-RD, [18][19][20][21][22][23][24] we identified a group with fovea-sparing (n ¼ 10; ages and compared their function and structural findings with those of the PRD patients (Supplementary Material). Eight patients with the diagnosis of RP or Usher syndrome but without a pericentral disease expression (ages 9-58) were also included for comparison of optical coherence tomography (OCT) results.…”

Section: Methods Subjectsmentioning

confidence: 99%

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Matsui

Cideciyan

Schwartz

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Patients were screened for an annular ring scotoma ranging from 38 to 408 (n ¼ 28, ages 24-71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed.RESULTS. Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density.CONCLUSIONS. Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone-rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity.

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“…SW-cone sensitivity measurements were made according to published methods (53). Techniques, methods of data analysis, and normal results have been described (25,30,(47)(48)(49)52).…”

Section: Methodsmentioning

confidence: 99%

“…Normal visual acuity is mediated at the fovea, where the highest spatial density of cone photoreceptors resides (20,27). Reduced acuity can relate to a dysfunctional fovea (28,29) or by the adoption of extrafoveal retina for fixation to compensate for dysfunction or degeneration of foveal cones (30). Correspondence of the center of the anatomical fovea to fixation was evaluated by optical coherence tomography (OCT) in all patients.…”

Section: Isomerase-deficient Human Retina In Rpe65-lca Showed Early Conementioning

confidence: 99%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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138

144

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The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.optical coherence tomography ͉ retinal degeneration ͉ retinoid cycle ͉ Leber congenital amaurosis ͉ gene therapy V ertebrate retinas have two types of photoreceptors: rods for the perception of dim light and cones for the perception of bright light. Light absorbed by visual pigments of photoreceptors triggers a series of enzymatic reactions known as phototransduction (1). The light-capturing part of the visual pigment, the chromophore, must then be regenerated. The pathway for regeneration of rhodopsin (the rod visual pigment) is known as the visual (retinoid) cycle (2, 3) and involves both rod cells and the adjacent retinal pigment epithelium (RPE). All-trans-retinal is reisomerized to 11-cis-retinal by a reaction in the RPE that requires the retinal isomerase, retinal pigment epithelium-specific 65-kDa protein (RPE65), and lecithinretinol acyltransferase (LRAT) activities. Functional visual pigment is then reformed by combining the 11-cis-chromophore with the photoreceptor opsin apoprotein (4). Molecular knowledge of the visual cycle has increased as the genes encoding the enzymes of this pathway have been elucidated (2, 5, 6).Decades ago, cone pigment regeneration was proposed to be RPE cell-independent (7, 8). More recently, cone-dominant ground squirrel and chicken retinas have been shown to exhibit retinoid isomerase activity that is distinct from RPE65 (5, 9, 10). Murine double knockout experiments, however, provide evidence that RPE65 and the RPE are essential for cone function (11...

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ABCA4-Associated Retinal Degenerations Spare Structure and Function of the Human Parapapillary Retina

Cited by 114 publications

References 60 publications

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in theABCA4Gene

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in theABCA4Gene

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Human cone photoreceptor dependence on RPE65 isomerase

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