Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease

Nasonkin, Igor O.; Illing, Michelle; Köehler, Michael; Schmid, Michael; Molday, Robert S.; Weber, Bernhard H. F.

doi:10.1007/s004390050649

Cited by 89 publications

(62 citation statements)

References 28 publications

(47 reference statements)

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“…7 Mutations in the ATP-binding cassette subfamily A group 4 (ABCA4) gene give rise to the recessive form of STGD, but are also associated with other retinal degenerative disorders such as cone-rod dystrophy (CRD) and autosomal recessive retinitis pigmentosa (arRP), 2,8,9 thereby characterising these dystrophies as ABCA4-associated retinopathies (AARs). 3,[10][11][12] It is proposed that malfunctioning ABCA4 protein prevents complete removal of retinoid products from the outer segment disc membrane of photoreceptors, resulting in the accumulation of downstream derivatives such as di-retinoid-ethanolamine in the retinal pigment epithelium (RPE). Such products can trigger RPE dysfunction through various mechanisms, consequently leading to degeneration of photoreceptors and ultimately vision loss.…”

Section: Introductionmentioning

confidence: 99%

Stargardt Disease: towards developing a model to predict phenotype

et al. 2013

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Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype-phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype-phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.

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Section: Introductionmentioning

confidence: 99%

Stargardt Disease: towards developing a model to predict phenotype

et al. 2013

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“…Two very large cytoplasmic domains are present: one comprises the N terminus; the other, suggested to be a regulatory domain (R), is interrupted by a highly hydrophobic segment (HH1) that is envisioned to partially insert into the lipid bilayer in a hairpin loop. B, topological model proposed by Illing et al (1,10) for ABCR. In this model, the N-terminal half contains a transmembrane segment designated H1 near the N terminus.…”

Section: Methodsmentioning

confidence: 99%

Membrane Topology of the ATP Binding Cassette Transporter ABCR and Its Relationship to ABC1 and Related ABCA Transporters

Bungert¹,

Molday²,

Molday

2001

Journal of Biological Chemistry

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153

130

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ABCR is a member of the ABCA subclass of ATP binding cassette transporters that is responsible for Stargardt macular disease and implicated in retinal transport across photoreceptor disc membranes. It consists of a single polypeptide chain arranged in two tandem halves, each having a multi-spanning membrane domain followed by a nucleotide binding domain. To delineate between several proposed membrane topological models, we have identified the exocytoplasmic (extracellular/lumen) N-linked glycosylation sites on ABCR. Using trypsin digestion, site-directed mutagenesis, concanavalin A binding, and endoglycosidase digestion, we show that ABCR contains eight glycosylation sites. Four sites reside in a 600-amino acid exocytoplasmic domain of the N-terminal half between the first transmembrane segment H1 and the first multi-spanning membrane domain, and four sites are in a 275-amino acid domain of the C half between transmembrane segment H7 and the second multi-spanning membrane domain. This leads to a model in which each half has a transmembrane segment followed by a large exocytoplasmic domain, a multi-spanning membrane domain, and a nucleotide binding domain. Other ABCA transporters, including ABC1 linked to Tangier disease, are proposed to have a similar membrane topology based on sequence similarity to ABCR. Studies also suggest that the N and C halves of ABCR are linked through disulfide bonds.ABCR, formerly known as the rim protein, is an ATP binding cassette (ABC) 1 transporter found in vertebrate retinal photoreceptor cells (1-3). It is localized along the rim region of photoreceptor rod outer segment disc membranes (1, 4, 5) and more recently has been found in human foveal and peripheral cone outer segments (6). Several studies have implicated ABCR in the retinoid cycle, possibly functioning as a retinal extruder or retinal-phosphatidylethanolamine flippase to facilitate the removal of all-trans-retinal from disc membranes following the photobleaching of rhodopsin (7-9).Mutations in the ABCA4 gene encoding ABCR have been linked to Stargardt disease, a relatively common juvenile macular dystrophy characterized by a decrease in visual acuity, progressive bilateral atrophy of the central retina, and the accumulation of yellow deposits within the retinal pigment epithelial cell layer (2, 10 -13). Mutations in ABCA4 have also been linked to related disease variants, including late-onset fundus flavimaculatus (14), cone-rod dystrophy (15), retinitis pigmentosa-like dystrophy (16, 17), and age-related macular degeneration (18), although the latter remains controversial (19).ABCR is a member of the ABCA subclass of ABC transporters (20). Like most other mammalian ABC transporters, members of this subclass consist of a single long polypeptide chain organized into two tandemly arranged halves. Each half contains a membrane-spanning domain (MSD) followed by a cytoplasmic nucleotide binding domain (NBD). The ABCA subclass is distinguished from other ABC transporter subclasses by the presence of a large domain between the...

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“…Not surprisingly, disrupting both rdh11 and rdh5 genes did not elicit the white punctata in the fundus that is observed in patients with RDH5 mutations (data not shown). A number of mice models are providing evidence that disruption of genes known to play a role in the retinoid cycle exhibit a more severe degenerative retinal pathology in humans compared with mice, such as abcr (42,43), cralbp (44,45), and rgr (24,46) mutations. These mouse models exhibit delayed dark adaptation kinetics at higher bleaching intensities but normal ERG kinetics under darkadapted conditions.…”

Section: ϫ9mentioning

confidence: 99%

Delayed Dark Adaptation in 11-cis-Retinol Dehydrogenase-deficient Mice

Kim

Maeda

et al. 2005

Journal of Biological Chemistry

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The oxidation of 11-cis-retinol to 11-cis-retinal in the retinal pigment epithelium (RPE) represents the final step in a metabolic cycle that culminates in visual pigment regeneration. Retinol dehydrogenase 5 (RDH5) is responsible for a majority of the 11-cis-RDH activity in the RPE, but the formation of 11-cis-retinal in rdh5 ؊/؊ mice suggests another enzyme(s) is present. We have previously shown that RDH11 is also highly expressed in RPE cells and has dual specificity for both cis-and trans-retinoid substrates. To investigate the role of RDH11 in the retinoid cycle, we generated rdh11

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Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease

Cited by 89 publications

References 28 publications

Stargardt Disease: towards developing a model to predict phenotype

Stargardt Disease: towards developing a model to predict phenotype

Membrane Topology of the ATP Binding Cassette Transporter ABCR and Its Relationship to ABC1 and Related ABCA Transporters

Delayed Dark Adaptation in 11-cis-Retinol Dehydrogenase-deficient Mice

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