Alternative titles; symbols
HGNC Approved Gene Symbol: ABCA4
SNOMEDCT: 47673003, 70099003, 716663009; ICD10CM: H35.53;
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:93,992,834-94,121,148 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22.1 | {Macular degeneration, age-related, 2} | 153800 | Autosomal dominant | 3 |
| Cone-rod dystrophy 3 | 604116 | Autosomal recessive | 3 | |
| Fundus flavimaculatus | 248200 | Autosomal recessive | 3 | |
| Retinal dystrophy, early-onset severe | 248200 | Autosomal recessive | 3 | |
| Retinitis pigmentosa 19 | 601718 | Autosomal recessive | 3 | |
| Stargardt disease 1 | 248200 | Autosomal recessive | 3 |
The ABCA4 gene produces an ATP-binding cassette (ABC) superfamily transmembrane protein expressed exclusively in retinal photoreceptors that is involved in clearance from photoreceptor cells of all-trans-retinal aldehyde (atRAL), a byproduct of the retinoid cycle of vision (Sun et al., 1999; Cideciyan et al., 2009).
Allikmets et al. (1997) identified the ABCR gene among expressed sequence tags obtained from human retina. ABCR was found to be closely related to the mouse and human ABC1 (600046) and ABC2 (600047) genes. The ABCR gene was not expressed detectably in any of 50 nonretinal fetal and adult tissues examined. Other studies indicated that the gene is uniquely retina-specific. The transcript size was estimated to be 8 kb. Allikmets et al. (1997) reported the complete sequence of the 6,705-bp ABCR coding region and the predicted 2,235-amino acid polypeptide encoded by it.
Allikmets et al. (1998) revised the estimate of the size of the ABCR gene to 6,819 bp encoding a 2,273-amino acid protein.
By genomic sequence analysis, Gerber et al. (1998) and Allikmets et al. (1998) determined that the ABCA4 gene contains at least 50 exons and spans an estimated 150 kb. Exon sizes range from 33 bp to 266 bp.
Using a whole genome radiation hybrid panel, Allikmets et al. (1997) mapped the ABCR gene to 1p21-p13, close to microsatellite markers D1S236 and D1S188. They further refined the localization by screening YACs from the described contig between these anonymous markers. These YACs delineated a region containing the Stargardt disease gene.
Azarian and Travis (1997) mapped the human photoreceptor rim protein gene (RMP) to chromosome 1 by radiation hybrid analysis. By homology, they mapped the mouse Rmp gene to chromosome 3 between the Ly37 and Tshb loci. Nasonkin et al. (1998) refined the map position of the human ABCR gene to 1p22.1-p21 by fluorescence in situ hybridization. By contig mapping, Allikmets et al. (1998) localized the ABCR gene to chromosome 1p22.3-p22.2 between markers D1S3361 and D1S236.
Gross (2014) mapped the ABCA4 gene to chromosome 1p22.1 based on an alignment of the ABCA4 sequence (GenBank AF001945) with the genomic sequence (GRCh37).
The ATP-binding cassette (ABC) superfamily includes genes whose products are transmembrane proteins involved in energy-dependent transport of a wide spectrum of substrates across membranes. Allikmets et al. (1997) noted that many disease-causing members of this superfamily result in defects in the transport of specific substrates, e.g., CFTR (602421), ALD (300100), SUR (600509), PMP70 (170995), and TAP2 (170261). In eukaryotes, ABC genes typically encode 4 domains that include 2 conserved ATP-binding domains and 2 domains with multiple transmembrane segments. The ATP-binding domains of the ABC genes contain motifs of characteristic conserved residues (Walker A and B motifs) spaced by 90 to 120 amino acids. Both this conserved spacing and the 'signature' or 'C' motif just upstream of the Walker B site distinguish members of the ABC superfamily from other ATP-binding proteins. These features allowed the isolation of new ABC genes by hybridization, degenerate PCR, and inspection of DNA sequence databases. Allikmets et al. (1996) characterized 21 members of the ABC superfamily by determining their map locations and patterns of expression.
Allikmets et al. (1997) localized ABCR transcripts exclusively within photoreceptor cells, indicating that ABCR mediates the transport of an essential molecule (or ion) either into or out of photoreceptor cells.
The ABCR gene is expressed exclusively in the retina, and in situ hybridization localized ABCR transcripts to rod photoreceptor cells. Sun and Nathans (1997) further localized ABCR to the disc membrane of retinal rod outer segments. The observations narrowed the range of plausible functions for ABCR and the corresponding range of pathogenic mechanisms underlying Stargardt disease (STGD; 248200). The authors commented that the accumulation of lipofuscin in the retinal pigment epithelium in Stargardt disease might reflect a defective ABCR-mediated transport of retinoids within the rod outer segment.
Allikmets et al. (1997) commented that the accumulation in the retinal pigment epithelium (RPE) of a lipofuscin-like substance in STGD suggests that the site of ABCR-mediated transport may be on the apical face of the photoreceptor cell and that this transport may affect exchange between the RPE and the photoreceptors.
To search for natural and artificial substrates and/or allosteric regulators of ABCR, Sun et al. (1999) solubilized and functionally reconstituted the purified protein into lipid membranes and surveyed a group of structurally diverse compounds for their ability to stimulate or inhibit ABCR ATPase activity. They observed that all-trans-retinal stimulated the ATPase activity of ABCR 3- to 4-fold. 11-cis- and 13-cis-retinal showed similar activity. All-trans-retinal stimulated the ATPase activity of ABCR with Michaelis-Menten behavior indicative of simple noncooperative binding associated with a rate-limiting enzyme-substrate intermediate in the pathway of ATP hydrolysis. Sun et al. (1999) concluded that these and other findings supported the hypothesis that various geometric isomers of retinal and/or other retinoids are transported by ABCR in a reaction that is coupled to ATP hydrolysis. The kinetic behavior implied that all-trans-retinal binds to an intermediate in the ATPase reaction pathway and that this binding accelerates a rate-limiting step in ATP hydrolysis and/or release of the hydrolysis products.
Korschen et al. (1999) identified glutamic acid-rich proteins (GARPs; see 600724) as multivalent proteins that interact with the key players of cGMP signaling, phosphodiesterase (see 602676) and guanylate cyclase (see 600179), and with ABCR, through 4 short repetitive sequences. In electron micrographs, GARPs are restricted to the rim region and incisures of discs in close proximity to the guanylate cyclase and ABCR, whereas the phosphodiesterase is randomly distributed. Korschen et al. (1999) concluded that the GARPs organize a dynamic protein complex near the disc rim that may control cGMP turnover and possibly other light-dependent processes.
Molday et al. (2000) showed by immunofluorescence microscopy and Western blot analysis that ABCR is present in foveal and peripheral cone, as well as rod, photoreceptors. The results suggested that the loss in central vision experienced by patients with Stargardt macular dystrophy arises directly from ABCR-mediated foveal cone degeneration.
The aldehyde group of all-trans-retinal reacts with the primary amine of phosphatidylethanolamine (PE) to form an equilibrium mixture of N-retinylidene-PE and all-trans-retinal. Beharry et al. (2004) isolated Abca4 from bovine rod outer segment disc membranes, and using HPLC and radiolabeled substrates, they found that Abca4 bound N-retinylidene-PE and all-trans-retinal. ATP and GTP released these retinoids from Abca4, but ADP, GDP, and nonhydrolyzable derivatives did not. N-retinyl-PE, the reduced form of N-retinylidene-PE, also bound Abca4, and all-trans-retinal bound Abca4 in the absence of PE. All-trans-retinol did not bind Abca4. Beharry et al. (2004) concluded that ABCA4 functions as a flippase to translocate N-retinylidene-PE from the lumen to the cytoplasmic side of retinal disc membranes.
Summaries of Mutations
Allikmets (2000) gave a tally of all ABCR alleles as 350 to 400, making the heterogeneity of ABCR comparable to that of another member of the ABC superfamily, the cystic fibrosis transmembrane conductance regulator (CFTR). Allelic variations in ABCR are the most prominent cause of retinal dystrophies with mendelian inheritance patterns.
Sun et al. (2000) listed 37 reported naturally occurring ABCA4 mutations. By studying expression of ABCR variants in transiently transfected 293 cells, they observed a wide spectrum of biochemical defects in these variants and provided insight into the transport mechanism of ABCR.
Stargardt Disease 1
Allikmets et al. (1997) performed mutation analysis of the ABCR gene in 48 families with Stargardt macular dystrophy (STGD1; 248200) previously ascertained by strict definitional criteria and shown to be linked to 1p. Using a total of 21 exons, they identified 19 different mutations (see, e.g., 601691.0001-601691.0005), the majority representing missense mutations in conserved amino acid positions. However, they also found several 1- to 2-bp insertions and deletions representing frameshifts. Two missense alterations (D847H; R943Q, 601691.0035) were found in at least 1 control individual, suggesting that they are neutral polymorphisms. The remaining mutations were found only in STGD patients and not in at least 40 unrelated normal controls (80 chromosomes). The mutations were scattered throughout the coding sequence of the ABCR gene. Most of the patients were found to be compound heterozygotes but 2 consanguineous families (1 Saudi Arabian (601691.0002) and 1 North American) were homozygous. In an erratum, Allikmets et al. (1997) provided a correction of the numbering system for mutations in the ABCR gene in Stargardt macular dystrophy. Sequencing of ABCR cDNA clones revealed an additional 114-bp exon after position 4352. This exon adds 38 in-frame amino acids to the polypeptide and represents the major transcript. See 601691.0004 and 601691.0005.
Nasonkin et al. (1998) reported 4 mutations in the ABCR gene in patients with Stargardt disease: 3106G-A (601691.0011), 3211insGT (601691.0012), 2565G-A (601691.0013), and 6079C-T (601691.0004).
Lewis et al. (1999) reported results of mutation scanning and direct DNA sequencing of all 50 exons of ABCR in 150 families segregating autosomal recessive Stargardt disease. ABCR variations were identified in 173 (57%) disease chromosomes, most of which represented missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but did cosegregate with the disease in these families with STGD1, and many occurred in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appeared to be associated with earlier onset of the disease and may represent misfolding alleles. The 2 most common mutant alleles, gly1961 to glu (601691.0007) and ala1038 to val (601691.0016), each identified in 16 of 173 disease chromosomes, represented 18.5% of mutations identified. G1961E in heterozygous state had previously been associated, at a statistically significant level, with age-related macular degeneration (ARMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of ARMD in first- and second-degree relatives. These findings supported the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some ABCR mutations in heterozygous state may enhance susceptibility to ARMD.
Rivera et al. (2000) studied 144 patients with Stargardt disease and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, they studied 200 individuals with ARMD to assess the possible role of ABCA4 in that disorder. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, they identified a total of 127 unique alterations, of which 90 had not previously been reported, and classified 72 as probable pathogenic mutations. Of the 288 Stargardt disease chromosomes studied, mutations were identified in 166, representing a detection rate of approximately 58%. Eight different alleles accounted for 61% of the identified disease alleles, and at least 1 of these, the L541P/A1038V complex allele (601691.0023), appeared to be a founder mutation in the German population. When the group with ARMD and the control group were analyzed with the same methodology, 18 patients with ARMD and 12 controls were found to harbor possible disease-associated alterations. This represented no significant difference between the 2 groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.
Yatsenko et al. (2001) tested the hypothesis that patients with late-onset Stargardt disease, i.e., onset at 35 years or later, retained partial ABCR activity attributable to mild missense alleles. They approached this study by in vivo functional analysis of various combinations of mutant alleles. They directly sequenced the entire coding region of ABCR and detected mutations in 33 of 50 (66%) disease chromosomes, but surprisingly, 11 of 33 (33%) were truncating alleles. Importantly, all 22 missense mutations were located outside the known functional domains of ABCR (ATP-binding or transmembrane), whereas in the general cohort of STGD1 subjects studied by Lewis et al. (1999), alterations occurred with equal frequency across the entire protein. Yatsenko et al. (2001) suggested that these missense mutations in regions of unknown function are milder alleles and are more susceptible to modifier effects. Thus, they corroborated a prediction from the model of ABCR pathogenicity that (1) one mutant ABCR allele is always missense in late-onset STGD1 patients, and (2) the age of onset is correlated with the amount of ABCR activity of this allele. In addition, they reported 3 new pseudodominant families, bringing the total to 8 of 178 outbred STGD1 families, and suggested a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (approximately 1 in 22).
Using double gradient-denaturing gradient gel electrophoresis (DG-DGGE), Fumagalli et al. (2001) performed a mutation screen in 44 Italian autosomal recessive Stargardt disease patients corresponding to 36 independent genomes. In 34 of the 36 patients (94.4%), 37 sequence changes were identified, including 26 missense, 6 frameshift, 3 splicing, and 2 nonsense variations. Twenty of the 37 mutations had not previously been described. There appeared to exist a subset of molecular defects specific to the Italian population. The identification of at least 2 disease-associated mutations in 4 healthy control individuals indicated a higher than expected carrier frequency of variant ABCR alleles in the general population. Genotype-phenotype analysis showed a possible correlation between the nature and location of some mutations and specific ophthalmoscopic features of STGD disease.
Fingert et al. (2006) reported a case of Stargardt disease in a patient homozygous for a mutation in the ABCA4 gene (601691.0026) as a result of uniparental isodisomy of chromosome 1. The patient's father was heterozygous for the mutation.
Singh et al. (2006) identified homozygous null mutations in the ABCA4 gene (601691.0028-601691.0029) in affected members of 2 Indian families with early-onset severe retinal dystrophy.
Albert et al. (2018) studied 2 deep intronic mutations in the ABCA4 gene, c.4539+2001G-A (M1) and c.4539+2028C-T (M2), each of which had been previously detected in patients with STGD1, in compound heterozygosity with another ABCA4 mutation. Analysis of mRNA transcripts from patient fibroblast-derived photoreceptor precursor cells showed that transcripts from M1 and M2 both included a 345-bp pseudoexon containing a premature termination codon (Arg1514LeufsTer36). The authors designed 4 antisense oligonucleotides (AONs) targeting the 345-bp pseudoexon for use in a therapeutic approach based on modulation of ABCA4 pre-mRNA splicing. They found that AON4 resulted in approximately 75% pseudoexon skipping in both M1 and M2 cell lines, whereas another, designated AON1, was very efficient only in the M1 cell line. The remaining 2 AONs were less effective. Analysis of ABCA4 mRNA levels of all alleles indicated that AON treatment increased the wildtype transcript levels of the M1 and M2 alleles. The authors concluded that AONs are a potential therapeutic tool for Stargardt disease.
Lee et al. (2019) reported a family in which the proband exhibited features of Stargardt disease and had more severe disease than her affected mother. The proband and her mother were heterozygous for a missense mutation in the PROM1 gene (R134C; 604365.0007), and the proband additionally carried a heterozygous splicing mutation in the ABCA4 gene (601691.0010) that was inherited from her asymptomatic mildly affected father. Copy number variant analysis of ABCA4 did not reveal any further variation. The authors stated that they could not unequivocally attribute the STGD1-like flecks observed in the father's fundus to the ABCA4 mutation; they concluded that monoallelic variation is not sufficient for disease, but that certain mutations may cause mild late-onset manifestation of STGD1 subphenotypes.
Lee et al. (2021) examined the full sequence of the ABCA4 gene in 644 individuals with STGD1 and found that 150 of them were compound heterozygous (140) or homozygous (10) for the G1961E (601691.0007) mutation. Twenty-three of these 150 patients harbored an intronic variant (c.769-784C-T) on the same allele as G1961E, including 1 G1961E/c.769-784C-T homozygote and 22 G1961E/c.769-784C-T heterozygotes. Lee et al. (2021) noted that the c.769-784C-T variant had been shown to affect mRNA splicing, leading to a moderate reduction in ABCA4 protein (Runhart et al., 2019). Lee et al. (2021) found that the G1961E/c.769-784C-T complex allele occurred at a higher frequency in compound heterozygous patients with nondeleterious variants in trans compared to deleterious variants in trans, suggesting that having a deleterious variant in trans with G1961E offsets the necessity for the c.769-784C-T modifier for disease penetrance. Lee et al. (2021) found that the presence of the G1061E/c.769-784C-T complex allele in the ABCA4 gene led to a more severe phenotype than G1061E in patients when in homozygous state or in compound heterozygous state with other mutations in ABCA4. Lee et al. (2021) concluded that the c.769-784C-T variant is an important cis-acting modifier of the G1961E mutation, and that the absence of such a variant on most G1961E alleles underlies the relative lack of affected G1961E homozygotes identified in patients with STGD1.
Age-Related Macular Degeneration
Age-related macular degeneration (ARMD; see 153800) is the leading cause of severe central visual impairment among the elderly and is associated both with environmental factors such as smoking and with genetic factors. Allikmets et al. (1997) screened 167 unrelated ARMD patients for alterations in the ABCR gene. Thirteen different ARMD-associated alterations, both deletions and amino acid substitutions (e.g., 601691.0006), were found in 1 allele of ABCR in 26 patients (16%). The authors suggested that identification of ABCR alterations will permit presymptomatic testing for high-risk individuals and may lead to earlier diagnosis of ARMD and to new strategies for prevention and therapy.
De La Paz et al. (1999) screened their patients with ARMD (159 familial cases from 112 multiple families and 53 sporadic cases) and 56 racially matched individuals with no known history of ARMD for evidence of mutation in the ABCR gene. The authors identified only 2 of the previously reported variants in their study population. Both variants occurred in sporadic cases, and none was found in familial cases or in the randomly selected population. In addition, the authors identified several previously undescribed polymorphisms and variants in both the ARMD and control populations. The authors concluded that mutation in the ABCR gene is not a major genetic risk factor for ARMD in their study population.
Shroyer et al. (1999) analyzed the ABCA4 gene in a 3-generation family manifesting both Stargardt disease and ARMD, and identified heterozygosity for a missense mutation (P1380L; 601691.0026) in the paternal grandmother with ARMD, whereas the proband and his 2 paternal cousins with Stargardt disease were compound heterozygous for the P1380L mutation and another missense mutation (601691.0036 and 601691.0037, respectively) in the ABCA4 gene. Shroyer et al. (1999) suggested that carrier relatives of STGD patients may have an increased risk of developing ARMD.
Allikmets and the International ABCR Screening Consortium (2000) tested the original hypothesis that ABCR is a dominant susceptibility locus for ARMD by screening 1,218 unrelated ARMD patients of North American and western European origin and 1,258 comparison individuals from 15 centers in North America and Europe for the 2 most frequent ARMD-associated variants found in ABCR: G1961E (601691.0007) and D2177N (601691.0006). One or the other of these sequence changes was found in 1 allele of ABCR in 40 patients (3.4%) and in 13 control subjects (0.95%). These differences were considered statistically significant. The risk of ARMD was elevated approximately 3-fold in D2177N carriers and approximately 5-fold in G1961E carriers.
By mutation analysis in a cohort of families that manifested both STGD and ARMD, Shroyer et al. (2001) found that ARMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. Shroyer et al. (2001) used an in vitro biochemical assay to test for protein expression and ATP-binding defects, and found that mutations associated with ARMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with ARMD, 16 (76%) showed abnormalities in protein expression, ATP binding, or ATPase activity. They inferred that carrier relatives of STGD patients are predisposed to develop ARMD.
Guymer et al. (2001) investigated the role of the G1961E (601691.0007) and D2177N (601691.0006) alleles of the ABCA4 gene in the pathogenesis of ARMD. They concluded that although the ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration, the alleles did not appear to be involved in a statistically significant fraction of ARMD cases.
Single-copy variants of the ABCR gene have been shown to confer enhanced susceptibility to ARMD. Bernstein et al. (2002) examined 19 of 33 sibs from 15 Stargardt families who carried their respective proband's variant ABCR allele. Some families exhibited concordance of ABCR alleles with the macular degeneration phenotype, but others did not. Exudative ARMD was uncommon among both probands and sibs.
Retinitis Pigmentosa 19
Martinez-Mir et al. (1998) demonstrated that the causative mutation in a family with retinitis pigmentosa-19 (RP19; 601718) was a frameshift (601691.0008) in the ABCR gene, which was present in homozygous state. The authors observed that the heterozygous parents, aged 72 and 82, in their family showed no signs of age-related macular dystrophy (ARMD). They thought, however, that this finding did not argue against haploinsufficiency of ABCR as the cause of ARMD; because this is a multifactorial disorder, ABCR haploinsufficiency may be only a predisposing factor, and not all parents of patients have ARMD. ABCR expression is confined to rods, and the fact that these photoreceptors are the cell type primarily affected in RP support ABCR as the gene responsible for RP19. They pointed out that the highest concentration of rods is 5 mm out from the fovea, within the zone that is affected in macular degeneration. If the rods in Stargardt disease and age-related macular degeneration produce an aberrant product, it would be expected to reach its highest concentration in this region. Persons with 1 wildtype and 1 mutant ABCR allele would be predisposed to a late-onset accumulation of cellular debris (drusen) and the development of ARMD.
Cone-Rod Dystrophy 3
To evaluate the importance of the ABCA4 gene as a cause of autosomal recessive cone-rod dystrophy (CORD3; 604116), Maugeri et al. (2000) studied 5 patients with autosomal recessive CORD and 15 patients with isolated CORD, all from Germany and the Netherlands. They found 19 ABCA4 mutations in 13 (65%) of 20 patients. In 6 patients, mutations were identified in both ABCA4 alleles; in 7 patients, mutations were detected in 1 allele. The complex ABCA4 allele L541P/A1038V (601691.0023) was found exclusively in German patients with CORD; 1 patient carried this complex allele in homozygous state, and 5 others were compound heterozygous.
Following the studies of Maugeri et al. (2000), Ducroq et al. (2002) evaluated the prevalence of ABCA4 mutations in a cohort of 55 patients with autosomal recessive or sporadic cone-rod dystrophy. They screened the 50 exons of the ABCA4 gene as well as the flanking intronic sequences using DHPLC and identified 16 different mutant alleles in 13 (23.6%) of 55 patients. Among these 13 patients, 2 were homozygotes (from 2 consanguineous families; see, e.g., 601691.0024), 4 were compound heterozygotes, and 7 were simple heterozygotes. There was no significant difference in the frequency of ABCA4 mutations between autosomal recessive and sporadic cases of CORD (6 of 29 versus 7 of 26 cases, respectively). Ducroq et al. (2002) estimated that this screen detected approximately 80% of mutations present in these families, with unidentified mutations potentially located in promoter or intron sequences or in undiscovered exons, and stated that the corrected mutation frequency would then be 29.5% of all CORD cases. For a sporadic case of cone-rod dystrophy with no ABCA4 mutation, they estimated that the risk of the disease being inherited as an autosomal recessive condition can be estimated to be 15.6% using the Bayesian calculation.
Fishman et al. (2003) examined 30 patients with autosomal recessive CORD, 16 of whom harbored plausible disease-causing variations in the ABCA4 gene. Among the mutation-positive patients, 2 distinctly different fundus phenotypes were observed: 12 showed diffuse pigmentary degenerative changes (type 1), whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration (type 2). All 16 patients showed either a central scotoma (6 patients) or both a central scotoma and some degree of peripheral field loss (10 patients). Both cone and rod a- and b-wave electroretinogram (ERG) amplitudes were reduced in all patients, which is diagnostic for CORD. Of the 12 patients classified as type 1, 4 harbored an A1038V change (601691.0016): in 2 this was the only sequence variation identified; in 1 case, it was observed in compound heterozygosity with a nonsense mutation; and in 1 case it was found as a complex allele with an L541P mutation (see 601691.0023). In the additional 8 patients classified as type 1, 2 showed 2 different heterozygous missense mutations, 3 had a single heterozygous missense mutation, and 3 had a heterozygous splice site mutation within intron 40 (601691.0010). In the 4 patients with considerably less funduscopically apparent pigmentary change (type 2), a heterozygous missense mutation was observed: in 2 instances L1201R (601691.0025), and in another 2 L2027F (601691.0004).
Ducroq et al. (2006) analyzed a large multiplex Christian Arab family with presumed autosomal recessive CORD and 6 consanguineous loops and found segregation of 3 distinct haplotypes at the CORD3 locus. Sequencing of the ABCA4 gene revealed 3 different mutations segregating with the disease in this family: 4 patients were homozygous for a splice site mutation; 4 were compound heterozygous for the splice site mutation and 1 of 2 missense mutations, respectively; and 1 patient was compound heterozygous for the 2 missense mutations. Ducroq et al. (2006) emphasized the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is high in the general population.
Kitiratschky et al. (2008) screened the ABCA4 gene in 64 patients with cone or cone-rod dystrophy and a family history consistent with autosomal recessive inheritance. They identified mutations in 20 (31%) of 64 patients, including 16 with CORD and 3 with cone dystrophy (see, e.g., 601690.0007, 601690.0010, and 601691.0030-601691.0033).
Susceptibility to Cleft Lip/Palate
For a discussion of a possible association between variation in the ABCA4 gene and susceptibility to nonsyndromic cleft lip/palate, see 119530.
Stargardt disease and late-onset fundus flavimaculatus (FFM) are autosomal recessive disorders leading to macular degeneration in childhood and adulthood, respectively. Rozet et al. (1998) screened the entire coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM families and showed that mutations truncating the ABCR protein consistently led to STGD. On the other hand, all mutations identified in FFM were missense mutations affecting uncharged amino acids. They stated that this was the first genotype/phenotype correlation in ABCR gene mutations.
Shroyer et al. (1999) reviewed ABCR mutations and the associated retinal diseases and proposed a model in which ABCR activity inversely correlates with severity of disease. In this model, truncating and severely misfolding mutations are associated with early-onset disease characterized by a primary photoreceptor loss and secondary retinal pigment epithelium (RPE) defects (retinitis pigmentosa and cone-rod dystrophy). In patients with milder mutations, photoreceptors are spared initially, but byproducts of faulty ABCR transport lead to accumulated material in the RPE and sequential photoreceptor loss (Stargardt disease and fundus flavimaculatus). Similarly, ABCR-associated ARMD might be due to the gradual accumulation of these same byproducts with eventual photoreceptor loss.
Klevering et al. (2004) described 3 Dutch families in which different combinations of retinal disorders occurred: ARMD, RP, and STGD in the first family, RP and STGD in the second family, and ARMD, CORD, and STGD in the third family. Three different mutations in the ABCA4 gene were identified in these families. In view of the relatively high carrier frequency of ABCA4 mutations (approximately 5%) in the general population, Klevering et al. (2004) concluded that the occurrence of various combinations of relatively rare retinal disorders in one family might not be as uncommon as once believed.
Wiszniewski et al. (2005) analyzed missense mutations (see, e.g., 601691.0023) in the photoreceptors of transgenic Xenopus laevis tadpoles and found mislocalization of ABCA4 protein. These mutations caused retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function. Patients with different retinal dystrophies harboring 2 misfolding alleles exhibit early age of onset (5 to 12 years) of retinal disease. Wiszniewski et al. (2005) suggested that a class of ABCA4 mutants may be an important determinant of the age of onset of retinal disease.
Valverde et al. (2007) screened for mutations in the ABCA4 gene in 60 patients in 50 Spanish families with different retinal dystrophies: 16 with autosomal recessive CORD, 27 with autosomal recessive retinitis pigmentosa, and 7 with autosomal dominant macular degeneration. Sixteen distinct variants were identified in 25 of the families. Thirteen of the CORD families had mutations in the ABCA4 gene; the most prevalent mutation in these families was a 2888delG mutation (601691.0027), accounting for 30% of the alleles detected. Putative disease-associated alleles were identified in 9 of the RP families and in 3 of the macular degeneration families.
In 66 individuals with known disease-causing ABCA4 alleles, Cideciyan et al. (2009) defined retina-wide disease expression by measuring rod and cone photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the nontruncating alleles were found to cause more severe disease than premature terminations, supporting the existence of a pathogenic component beyond simple loss of function.
By SDS-PAGE and immunoblot analysis of purified bovine and frog rod outer segments, Azarian and Travis (1997) identified 210- and 240-kD proteins, respectively, as RMP. By peptide microsequence analysis and degenerate primers for nested PCR on bovine and mouse retinal libraries, Azarian and Travis (1997) isolated a mouse Rmp cDNA encoding a putative 2,310-amino acid protein. Sequence analysis predicted 86% identity and 92% similarity of mouse RMP to human ABCR protein, 3 potential N-glycosylation sites, 12 membrane-spanning segments, 2 ABC transporter signature motifs with potential phosphorylation sites, and 2 consensus ATP/GTP nucleotide-binding sites. Northern blot analysis revealed expression exclusively in retina. Immunoblot analysis showed that RMP is expressed predominantly in the outer segments of retinal photoreceptors.
Weng et al. (1999) characterized the ocular phenotype in Abcr knockout mice. Mice lacking the Abcr gene showed delayed dark adaptation, increased all-trans-retinaldehyde (all-trans-RAL) following light exposure, elevated phosphatidylethanolamine (PE) in outer segments, accumulation of the protonated Schiff base complex of all-trans-RAL and PE (N-retinylidene-PE), and striking deposition of a major lipofuscin fluorophore (A2E) in retinal pigment epithelium (RPE). These data suggested that ABCR functions as an outwardly directed flippase for N-retinylidene-PE. Delayed dark adaptation is likely due to accumulation in discs of the noncovalent complex between opsin and all-trans-RAL. ABCR-mediated retinal degeneration in patients may result from 'poisoning' of the RPE due to A2E accumulation, with secondary photoreceptor degeneration due to loss of the ABCR support role.
The primary pathologic defect in Stargardt disease is accumulation of toxic lipofuscin pigments, such A2E, in cells of the RPE. This accumulation was thought to be responsible for the photoreceptor death and severe visual loss in patients with Stargardt disease. Sieving et al. (2001) found that treatment of rodents with isotretinoin (Accutane), an agent used in the treatment of acne, delayed rhodopsin regeneration and slowed recovery of rod sensitivity after light exposure. Importantly, isotretinoin did not cause photoreceptor degeneration and actually protected photoreceptors from light-induced damage. Light activation of rhodopsin results in its release of all-trans-retinaldehyde, which constitutes the first reactant in A2E biosynthesis. A side effect of treatment with isotretinoin is reduced night vision because of its inhibitory effect on 11-cis-retinol dehydrogenase (601617) in RPE cells. Radu et al. (2003) tested the effects of isotretinoin on lipofuscin accumulation in Abcr knockout mice, a model of recessive Stargardt disease. They observed by electron microscopy that isotretinoin blocked the formation of A2E biochemically and the accumulation of lipofuscin pigments. No significant visual loss was observed in Abcr-null mice by electroretinography. Isotretinoin also blocked the slower, age-dependent accumulation of lipofuscin in wildtype mice. The results suggested that treatment with isotretinoin may inhibit lipofuscin accumulation and delay the onset of visual loss in patients with Stargardt disease and may be an effective treatment for other forms of retinal or macular degeneration associated with lipofuscin accumulation.
In affected members of 3 families with Stargardt macular dystrophy (STGD1; 248200), Allikmets et al. (1997) found a 2588G-C transversion of the ABCR gene, predicting a gly863-to-ala (G863A) substitution.
In 40 western European patients with STGD, Maugeri et al. (1999) found 19 novel mutations in the ABCR gene. The 2588G-C transversion, identified in 15 (37.5%) patients, showed linkage disequilibrium with a rare 2828G-A polymorphism (R943Q; 601691.0035) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3-prime splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of 2 STGD patients with the 2588G-C mutation showed that the resulting mutant ABCR proteins either lack gly863 or contain the missense mutation gly863 to ala. Maugeri et al. (1999) hypothesized that the 2588G-C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This was supported by the fact that the accompanying ABCR mutation in at least 5 of the 8 STGD patients was null (severe) and that a combination of 2 mild mutations had not been observed among 68 STGD patients. The 2588G-C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, delta-F508, in the CFTR gene in cystic fibrosis (602421.0001). Given an STGD incidence of 1 in 10,000, homozygosity for the 2588G-C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.
Maugeri et al. (2002) studied 2,343 unrelated random control individuals from 11 European countries and 241 control individuals from the U.S. and found a carrier frequency of the 2588G-C mutation of 1 out of 54 and 1 out of 121, respectively. In Europe, an increasing gradient was observed from southwest (carrier frequency in Portugal: 0 out of 199) to northeast (carrier frequency in Sweden: 1 out of 18). Haplotype analysis in 16 families with STGD (12 Dutch, 3 German, and 1 of Swedish origin) segregating the 2588G-C mutation showed 4 intragenic SNPs invariably present in all disease chromosomes and sharing of the same allele for several microsatellite markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicated a single origin of the 2588G-C mutation, which was estimated to have occurred between 2,400 and 3,000 years ago. This study confirmed the 2588G-C mutation as one of the most frequent autosomal recessive disease mutations in the European population, with an origin somewhere in the north-northeastern parts of Europe. Maugeri et al. (2002) raised the possibility of a carrier advantage due to some unknown function of ABCA4 in nonocular tissues. The high carrier frequency of the 2588C allele in Sweden of 1 out of 18 was in striking contrast with the incidence of STGD, which apparently is not higher in that country than in the rest of Europe, and therefore supported the hypothesis that this mutation represents a mild allele which is not disease causing in homozygous state.
By enzyme-kinetic studies of mutations in the nucleotide-binding domain-1 (NBD1) of the ABCA4 gene, Suarez et al. (2002) showed that the G863Q mutation had a significant attenuation of the rate of nucleotide hydrolysis and nucleotide binding affinity compared to wildtype protein and the mild R943Q mutation.
Aberrant or modified splicing patterns of genes are causative for many human diseases. Hiller et al. (2004) described widespread occurrence of alternative splicing at NAGNAG acceptors. Hiller et al. (2006) reported a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, they extracted 64 SNPs that most likely affect alternative NAGNAG splicing. They demonstrated that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. Since 28% of the NAGNAG SNPs occurred in known disease genes, they represented preferred candidates for functional analysis. As an example of the disease relevance of a NAGNAG SNP, they cited the ABCA4 gene and the mutation described by Maugeri et al. (1999): a NAGNAG mutation (2588G/C, changing the acceptor site TAGGAG to TAGCAG) that has a high frequency in patients with STGD1. By experimental analysis of the splice patterns of 2 patients with STGD who carried the mutation and 1 control individual, they found that only the alleles with the TAGCAG produce 2 splice forms. The study of Hiller et al. (2006) would predict exactly this outcome of the mutation.
In an 18.5-year-old female with cone dystrophy (CORD3; 604116), in whom information on rod function was unavailable, Kitiratschky et al. (2008) identified compound heterozygosity for the G863A mutation and a splice site mutation (601690.0030). The patient, who had onset of disease at 18 years of age, had increased glare sensitivity and normal night vision, atrophy of RPE at the macula, central scotoma, and decreased cone response on electroretinography (ERG); information was unavailable on her color vision or on ERG rod function. Family members were not available for study.
In a Saudi Arabian patient (family KKESH214) with Stargardt macular dystrophy (STGD1; 248200) and likely consanguineous parents, Allikmets et al. (1997) identified homozygosity for a G-to-A transition at nucleotide 2791 in the ABCR gene, predicting a val931-to-met (V931M) amino acid change. The unaffected parents were heterozygous for the mutation.
In 5 families, Allikmets et al. (1997) found that individuals with Stargardt macular dystrophy (STGD1; 248200) had a C-to-T transition at nucleotide 3083 of the ABCR gene, predicting an ala1028-to-val (A1028V) amino acid substitution.
In 3 families, Allikmets et al. (1997) found that individuals with Stargardt macular dystrophy (STGD1; 248200) had a C-to-T transition at nucleotide 5965 of the ABCR gene, predicting a leu1989-to-phe (L1989F) amino acid substitution. In a correction of the numbering system for mutations, necessitated by the finding of an additional 114-bp exon after nucleotide position 4352, Allikmets et al. (1997) indicated that the mutation originally designated LEU1989PHE should be L2027F. In 2 sibs with Stargardt disease, Nasonkin et al. (1998) identified a 6079C-T transition, resulting in a leu2027-to-phe substitution.
Fishman et al. (2003) observed this mutation in 2 patients with cone-rod dystrophy (CORD3; 604116) who had comparatively mild funduscopically apparent pigmentary changes.
In 2 families with Stargardt disease (STGD1; 248200), Allikmets et al. (1997) found a G-to-C transversion at nucleotide 6034 of the ABCR gene, predicted to result in a val2012-to-leu (V2012L) substitution. In a correction to the numbering system, Allikmets et al. (1997) indicated that this mutation, originally designated V2012L, should be designated V2050L.
Allikmets et al. (1997) found an asp2177-to-asn (D2177N) mutation in the ABCR gene in 7 of 167 patients with age-related macular dystrophy (153800) and in only 1 of 220 controls. The associated retinal pathology ranged from fine macular cuticular drusen (age 62 years) to normal maculas but extensive extramacular and peripheral drusen (ages 72 and 74 years, respectively), to geographic atrophy involving the central third of the macula in each eye (ages 61 to 86 years, respectively).
In 6 of 167 patients with age-related macular dystrophy (ARMD2; 153800), Allikmets et al. (1997) found a gly1961-to-glu (G1961E) alteration in the ABCR gene. The associated pathology ranged from a few tiny juxtafoveal drusen in 1 eye of a patient (age 74 years), to confluent drusen and drusenoid retinal pigment epithelium (RPE) detachments (age 78 years), to various forms of soft to calcified macular drusen and extensive geographic atrophy (more than 1 disc diameter) (ages 81 and 82 years, respectively).
In a study of 150 families with recessive Stargardt disease (STGD1; 248200), Lewis et al. (1999) found that the G1961E mutation was present in 16 of 173 chromosomes in which mutation was identified. G1961E in heterozygous state had previously been associated with age-related macular degeneration. In 150 families with STGD1, a high frequency of ARMD in first- and second-degree relatives was found, suggesting that heterozygosity enhances susceptibility to ARMD.
In a 14-year-old female with cone dystrophy (CORD3; 604116), Kitiratschky et al. (2008) identified compound heterozygosity for a 5882G-A transition in exon 42 of the ABCA4 gene, resulting in the G1961E substitution, and a splice site mutation (601691.0030). The patient, who had onset of disease at 6 years of age, had a red-green defect of color vision, normal glare sensitivity and night vision, RPE atrophy of the macula and peripheral retina, central scotoma, and a reduced cone but normal rod electroretinogram (ERG). Both mutations were also identified in her affected brother, and their unaffected parents were each heterozygous for 1 of the mutations, respectively.
Lek et al. (2016) questioned the pathogenicity of this variant because the ExAC database lists 4 homozygotes with the variant as well as a high allele frequency (0.015) of the variant in the South Asian population.
Martinez-Mir et al. (1997) demonstrated that one form of autosomal recessive retinitis pigmentosa (RP19; 601718) maps to 1p21-p13, the same region as that to which Stargardt disease and its somewhat milder variant, fundus flavimaculatus, map. In a family with RP19, Martinez-Mir et al. (1998) demonstrated a homozygous mutation in the ABCR gene, a 1-bp deletion at cDNA position 1847 (1847delA). The mutation generated a frameshift early in the coding region (codon 616 in exon 13) that added 32 new residues and a premature stop codon.
Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or cone-rod dystrophy (CORD3; 604116). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score = 4.22), a genomic segment that harbors the ABCA4 gene involved in Stargardt disease and age-related macular degeneration. In 4 RP patients in this family they found homozygosity for a 5-prime splice site mutation, IVS30+1G-T. The 5 patients with CORD in this family were compound heterozygotes for the IVS30+1G-T mutation and a 5-prime splice site mutation in intron 40: IVS40+5G-A (601691.0010). Both splice site mutations were found heterozygously in 2 unrelated STGD patients (in whom the second mutation was either a missense mutation or unknown), but not in 100 control individuals. Since no Stargardt patient had been reported to carry 2 ABCR null alleles and the RP phenotype was more severe than the STGD phenotype, Cremers et al. (1998) hypothesized that the intron 30 splice site mutation represented a true null allele. Since the intron 30 mutation was found heterozygously in the CORD patients, the intron 40 mutation probably rendered the exon 40 5-prime splice site partially functional. These results showed that mutations in the ABCR gene result not only in STGD and ARMD, but also in autosomal recessive RP and CORD.
Cremers et al. (1998) presented evidence that a 5-prime splice site mutation in intron 40 (IVS40+5G-A) in compound heterozygous state with the IVS30+1G-T mutation (601691.0009) in the ABCR gene can result in cone-rod dystrophy (CORD3; 604116).
In 3 patients with autosomal recessive CORD and diffuse pigmentary degenerative changes, Fishman et al. (2003) identified the IVS40+5G-A mutation.
In a 30-year-old man with cone dystrophy, Kitiratschky et al. (2008) identified compound heterozygosity for the IVS40 5714+5G-A splice site mutation and an L1940P substitution (601690.0033) in the ABCA4 gene. The patient, who had onset of disease at 7 years of age, had normal color vision, normal glare sensitivity and night vision, atrophy of the RPE and choroid as well as RPE clumping in the area of the macula, central scotoma, and a reduced cone but normal rod electroretinogram. Both mutations were also identified in his affected sister, and their unaffected mother was heterozygous for the L1940P mutation; information was unavailable on their father.
In an asymptomatic man with STGD1-like flecks in his fundus, Lee et al. (2019) identified heterozygosity for the IVS40+5G-A splicing mutation in the ABCA4 gene. His daughter, who exhibited severe Stargardt disease, was heterozygous for the ABCA4 splicing mutation as well as a missense mutation in the PROM1 gene (R134C; 604365.0007), inherited from her less severely affected mother. The authors stated that they could not unequivocally attribute the father's phenotype to the ABCA4 mutation; they concluded that monoallelic variation is not sufficient for disease, but that certain mutations may cause mild late-onset manifestation of STGD1 subphenotypes.
In a patient with Stargardt disease (STGD1; 248200), Nasonkin et al. (1998) identified a G-to-T transition at nucleotide 2565 of the ABCR gene, resulting in a stop at codon 855 (W855X).
In 2 sibs with Stargardt disease (STGD1; 248200), Nasonkin et al. (1998) identified a G-to-A transition at nucleotide 3106 of the ABCR gene, replacing the negatively charged glutamic acid with a positively charged lysine residue at codon 1036 (G1036K).
In 2 sibs with Stargardt disease (STGD1; 248200), Nasonkin et al. (1998) identified an insertion of 2 bases, GT, at nucleotide 3211 (3211insGT) of the ABCR gene, causing a frameshift at codon 1071 and leading to a protein termination 11 amino acids downstream.
In a family with fundus flavimaculatus (FFM; see 248200), Rozet et al. (1998) demonstrated that affected members were compound heterozygous for mutations in the ABCR gene: leu1970 to phe (L1970F), due to a 5908C-T transition, and leu1971 to arg (L1971R; 601691.0015), due to a 5912T-G transversion.
For discussion of the leu1971-to-arg mutation in the ABCR gene that was found in compound heterozygous state in affected members of a family with fundus flavimaculatus (FFM; see 248200) by Rozet et al. (1998), see 601691.0014.
In a study of 150 families segregating autosomal recessive Stargardt disease (STGD1; 248200), Lewis et al. (1999) found that the 2 most common mutant alleles in the ABCR gene, ala1038-to-val and gly1961-to-glu (601691.0007), each identified in 16 of 173 disease chromosomes, constituted 18.5% of the mutations identified.
Fishman et al. (2003) identified the A1038V mutation in 4 patients with cone-rod dystrophy (CORD3; 604116): in 2 this was the only sequence variation found; in 1 case, it was observed in compound heterozygosity with a nonsense mutation; and in 1 case it was found as a complex allele with an L541P mutation (see 601691.0023). Diffuse pigmentary degenerative changes were seen funduscopically in all 4 patients.
In a family segregating retinitis pigmentosa (RP19; 601718) and Stargardt disease (STGD1; 248200) in 2 first cousins, Rozet et al. (1999) found that compound heterozygosity for a splice acceptor site mutation of the ABCR gene, IVS13-1G-A, and an unknown mutation resulted in STGD1, whereas hemizygosity for the splice site mutation resulted in RP19. In the patient with RP19, a partial deletion of the maternal ABCR gene was presumed to be the source of a null allele, although this was not conclusively proven.
Shroyer et al. (2000) described a family showing pseudodominant inheritance of the autosomal recessive disorder Stargardt disease (STGD1; 248200). The mother had onset of symptoms at the age of 30 years and had compound heterozygous mutations in the ABCA4 gene: a 1018T-G transversion, resulting in a tyr340-to-asp (Y340D) mutation, and a 5338C-G transversion, resulting in a pro1780-to-ala (P1780A) mutation (601691.0034). Her 3 children with Stargardt disease were compound heterozygous for the Y340D mutation, and a complex mutation consisting of G863A (601691.0001)/R572Q (601691.0022)/R943Q (601691.0035) inherited from the father.
In a patient with Stargardt disease (STGD1; 248200), Gerber et al. (1998) identified a homozygous acceptor splice site mutation in the ABCA4 gene, an A-to-G change in intron 5 at position -2.
In a patient with Stargardt disease (STGD1; 248200), Gerber et al. (1998) identified a heterozygous C-to-T transition at nucleotide 634 in the ABCA4 gene, resulting in an arg212-to-cys substitution. The second mutation was not identified.
Paloma et al. (2001) noted that the R212C mutation had been found in French, Italian, Dutch, German, and Spanish patients but not in British patients.
In 2 patients with Stargardt disease (STGD1; 248200), Gerber et al. (1998) identified a homozygous C-to-T transition at nucleotide 52 in the ABCA4 gene, resulting in an arg18-to-trp substitution.
In a 2-generation pedigree demonstrating pseudodominant inheritance of Stargardt disease (STGD1; 248200), Shroyer et al. (2000) described compound heterozygous mutations in the ABCA4 gene: the Y340D mutation (601691.0018) and a complex allele consisting of a 1715G-A transition, resulting in an arg572-to-gln (R572Q) substitution, the G863A mutation (601691.0001), and the R943Q polymorphism (601691.0035). The 3 affected children in this family (AR31) inherited the Y340D mutation from their mother and the complex mutation from their father.
In a study of 144 patients with Stargardt disease in Germany, Rivera et al. (2000) found that 8 different mutations in the ABCA4 gene accounted for 61% of the identified disease (STGD1; 248200) alleles, and concluded that at least 1 of these, the leu541-to-pro/ala1038-to-val allele, was a founder mutation in this population. The mutation occurred on a single haplotype. The amino acid substitution leu541 to pro was caused by a T-to-C transition at nucleotide 1622 in exon 12.
Maugeri et al. (2000) found homozygosity for this complex allele in a German patient diagnosed as having cone-rod dystrophy (CORD3; 604116). They found it in compound heterozygous state in 5 other German patients with cone-rod dystrophy.
Fishman et al. (2003) identified this allele in a patient of German and Polish ancestry with CORD3. Diffuse pigmentary degenerative changes were apparent funduscopically.
Wiszniewski et al. (2005) analyzed a cohort of 29 arRP families for ABCA4 mutations and identified homozygosity for the complex L541P/A1038V allele in 2 affected individuals of 1 family (AR197) with retinitis pigmentosa-19 (RP19; 601718).
In a patient with cone-rod dystrophy (CORD3; 604116) from a consanguineous Portuguese family, Ducroq et al. (2002) found homozygosity for a frameshift mutation (2617delCT) in the ABCA4 gene.
In 2 patients with cone-rod dystrophy (CORD3; 604116) with comparatively mild funduscopically apparent pigmentary changes, Fishman et al. (2003) identified a heterozygous leu1201-to-arg mutation (L1201R) in the ABCA4 gene.
In a 3-generation family manifesting both Stargardt disease (STGD1; 248200) and age-related macular degeneration (ARMD2; 153800), Shroyer et al. (1999) identified heterozygosity for a 4139C-T transition in the ABCA4 gene, resulting in a pro1380-to-leu (P1380L) substitution, in the paternal grandmother with ARMD. The proband and his 2 paternal cousins, who all had Stargardt disease, were compound heterozygous for the P1380L mutation and a 2461T-A transversion in the ABCA4 gene, resulting in a trp821-to-arg (W821R; 601691.0036) substitution, and a 3365G-A transition in the ABCA4 gene, resulting in a glu1122-to-lys (E1122K; 601691.0037) substitution, respectively. Shroyer et al. (1999) suggested that carrier relatives of STGD patients may have an increased risk of developing ARMD.
In a female patient with Stargardt disease, Fingert et al. (2006) identified homozygosity for a pro1380-to-leu mutation in the ABCA4 gene caused by uniparental isodisomy of chromosome 1. Her father was heterozygous for the mutation and the mother was not a carrier.
Valverde et al. (2007) identified a 1-bp deletion (2888delG) in the ABCA4 gene in compound heterozygous or homozygous state in 4 of 13 Spanish patients with cone-rod dystrophy-3 (CORD3; 604116). The mutation leads to a frameshift that produces a stop codon.
In a brother and sister, born of consanguineous Indian parents, with early-onset severe retinal dystrophy (see 248200), Singh et al. (2006) identified homozygosity for a 1-bp deletion at nucleotide 1225 (1225delA) in exon 9 of the ABCA4 gene, resulting in a frameshift at arg409. The parents and an unaffected sib were heterozygous for the mutation, which was not found in 100 normal controls.
In 3 brothers, born of consanguineous Indian parents, with early-onset severe retinal dystrophy (see 248200), Singh et al. (2006) identified homozygosity for a 6088C-T transition in exon 44 of the ABCA4 gene, resulting in an arg2030-to-ter substitution. The parents and an unaffected sib were heterozygous for the mutation, which was not found in 100 normal controls.
In 6 patients with cone-rod dystrophy (CORD3; 604116), 1 with cone dystrophy, and 1 with cone dystrophy but no information on rod function, all of whom had a family history consistent with autosomal recessive inheritance, Kitiratschky et al. (2008) identified compound heterozygosity for a splice site mutation (5461-10T-C) in intron 39 and another mutation in the ABCA4 gene (see, e.g., 601690.0001 and 601690.0007). In 2 of the CORD3 patients, a mutation on the second allele was not detected; the authors noted that with the methods used, genomic rearrangement mutations could not be excluded.
In a 20-year-old woman with cone dystrophy (CORD3; 604116), Kitiratschky et al. (2008) identified compound heterozygosity for a 5285C-A transversion in exon 37 of the ABCA4 gene, resulting in an ala1762-to-asp (A1762D) substitution, and a 15-bp deletion (3539del15; 601690.0032) in exon 24 of the ABCA4 gene. The patient, who had onset of disease at 10 years of age, had a red-green defect of color vision, normal glare sensitivity and night vision, RPE atrophy of the macula and peripheral retina, central scotoma, and a reduced cone but normal rod electroretinogram (ERG). Both mutations were also identified in her affected sister, and their unaffected parents were each heterozygous for 1 of the mutations, respectively. The A1762D mutation had previously been found (Stenirri et al., 2004) in compound heterozygosity with another ABCA4 missense mutation in a patient with Stargardt disease (STGD1; 248200).
For discussion of the 15-bp deletion in the ABCA4 gene that was found in compound heterozygous state in patients with cone-rod dystrophy (CORD3; 604116) by Kitiratschky et al. (2008), see 601691.0031.
In 2 unrelated Spanish patients, one with fundus flavimaculatus (FFM; see 248200) and the other with early-onset Stargardt disease (STGD1; 248200), Paloma et al. (2001) identified heterozygosity for a mutation in exon 41 of the ABCA4 gene, resulting in a leu1940-to-pro (L1940P) substitution. The second disease allele remained unidentified in both patients.
In a 30-year-old man with cone dystrophy (CORD3; 604116), Kitiratschky et al. (2008) identified compound heterozygosity for a splice site mutation in intron 40 of the ABCA4 gene (601690.0010) and a 5819T-C transition in exon 41, resulting in the L1940P substitution.
For discussion of the pro1780-to-ala substitution (P1780A) in the ABCA4 gene that was found in compound heterozygous state in patients with Stargardt disease (STGD1; 248200) by Shroyer et al. (2000), see 601691.0018.
Allikmets et al. (1997) reported a 2828G-A transition in exon 19 of the ABCA4 gene, resulting in an arg943-to-gln (R943Q) substitution, as a neutral polymorphism in patients with Stargardt disease (STGD1; 248200) and controls. Subsequently, the R943Q variant was associated with mild forms of age-related macular degeneration (ARMD2; 153800) ( Allikmets et al., 1997). Maugeri et al. (1999) found that the R943Q variant was in linkage disequilibrium with the G863A mutation (601691.0001), suggesting a founder effect.
By enzyme-kinetic studies of mutations in the nucleotide-binding domain-1 (NBD1) of the ABCA4 gene, Suarez et al. (2002) showed that the R943Q mutation had a small but detectable reduction in nucleotidase activity and nucleotide binding affinity compared to wildtype protein.
For discussion of the trp821-to-arg (W821R) substitution in the ABCA4 gene that was found in compound heterozygous state in patients with Stargardt disease (STGD1; 248200) by Shroyer et al. (2000), see 601691.0026 and Shroyer et al. (1999).
For discussion of the glu1122-to-lys (E1122K) substitution in the ABCA4 gene that was found in compound heterozygous state in patients with Stargardt disease (STGD1; 248200) by Shroyer et al. (2000), see 601691.0026 and Shroyer et al. (1999).
Albert, S., Garanto, A., Sangermano, R., Khan, M., Bax, N. M., Hoyng, C. B., Zernant, J., Lee, W., Allikmets, R., Collin, R. W. J., Cremers, F. P. M. Identification and rescue of splice defects caused by two neighboring deep-intronic ABCA4 mutations underlying Stargardt disease. Am. J. Hum. Genet. 102: 517-527, 2018. [PubMed: 29526278] [Full Text: https://doi.org/10.1016/j.ajhg.2018.02.008]
Allikmets, R., Gerrard, B., Hutchinson, A., Dean, M. Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum. Molec. Genet. 5: 1649-1655, 1996. [PubMed: 8894702] [Full Text: https://doi.org/10.1093/hmg/5.10.1649]
Allikmets, R., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A., Zabriskie, N. A., Hutchinson, A., Dean, M., Lupski, J. R., Leppert, M. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277: 1805-1807, 1997. [PubMed: 9295268] [Full Text: https://doi.org/10.1126/science.277.5333.1805]
Allikmets, R., Singh, N., Sun, H., Shroyer, N. F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A., Rattner, A., Smallwood, P., Li, Y., Anderson, K. L., Lewis, R. A., Nathans, J., Leppert, M., Dean, M., Lupski, J. R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet. 15: 236-246, 1997. Note: Erratum: Nature Genet. 17: 122 only, 1997. [PubMed: 9054934] [Full Text: https://doi.org/10.1038/ng0397-236]
Allikmets, R., the International ABCR Screening Consortium. Further evidence for an association of ABCR alleles with age-related macular degeneration. Am. J. Hum. Genet. 67: 487-491, 2000. [PubMed: 10880298] [Full Text: https://doi.org/10.1086/303018]
Allikmets, R., Wasserman, W. W., Hutchinson, A., Smallwood, P., Nathans, J., Rogan, P. K., Schneider, T. D., Dean, M. Organization of the ABCR gene: analysis of promoter and splice junction sequences. Gene 215: 111-122, 1998. [PubMed: 9666097] [Full Text: https://doi.org/10.1016/s0378-1119(98)00269-8]
Allikmets, R. Simple and complex ABCR: genetic predisposition to retinal disease. (Editorial) Am. J. Hum. Genet. 67: 793-799, 2000. [PubMed: 10970771] [Full Text: https://doi.org/10.1086/303100]
Azarian, S. M., Travis, G. H. The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR). FEBS Lett. 409: 247-252, 1997. [PubMed: 9202155] [Full Text: https://doi.org/10.1016/s0014-5793(97)00517-6]
Beharry, S., Zhong, M., Molday, R. S. N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR). J. Biol. Chem. 279: 53972-53979, 2004. [PubMed: 15471866] [Full Text: https://doi.org/10.1074/jbc.M405216200]
Bernstein, P. S., Leppert, M., Singh, N., Dean, M., Lewis, R. A., Lupski, J. R., Allikmets, R., Seddon, J. M. Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings. Invest. Ophthal. Vis. Sci. 43: 466-473, 2002. [PubMed: 11818392]
Cideciyan, A. V., Swider, M., Aleman, T. S., Tsybovsky, Y., Schwartz, S. B., Windsor, E. A. M., Roman, A. J., Sumaroka, A., Steinberg, J. D., Jacobson, S. G., Stone, E. M., Palczewski, K. ABCA4 disease progression and a proposed strategy for gene therapy. Hum. Molec. Genet. 18: 931-941, 2009. [PubMed: 19074458] [Full Text: https://doi.org/10.1093/hmg/ddn421]
Cremers, F. P. M., van de Pol, D. J. R., van Driel, M., den Hollander, A. I., van Haren, F. J. J., Knoers, N. V. A. M., Tijmes, N., Bergen, A. A. B., Rohrschneider, K., Blankenagel, A., Pinckers, A. J. L. G., Deutman, A. F., Hoyng, C. B. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum. Molec. Genet. 7: 355-362, 1998. [PubMed: 9466990] [Full Text: https://doi.org/10.1093/hmg/7.3.355]
De La Paz, M. A., Guy, V. K., Abou-Donia, S., Heinis, R., Bracken, B., Vance, J. M., Gilbert, J. R., Gass, J. D. M., Haines, J. L., Pericak-Vance, M. A. Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration. Ophthalmology 106: 1531-1536, 1999. [PubMed: 10442900] [Full Text: https://doi.org/10.1016/S0161-6420(99)90449-9]
Ducroq, D., Rozet, J.-M., Gerber, S., Perrault, I., Barbet, F., Hanein, S., Hakiki, S., Dufier, J.-L., Munnich, A., Hamel, C., Kaplan, J. The ABCA4 gene in autosomal recessive cone-rod dystrophies. (Letter) Am. J. Hum. Genet. 71: 1480-1482, 2002. [PubMed: 12515255] [Full Text: https://doi.org/10.1086/344829]
Ducroq, D., Shalev, S., Habib, A., Munnich, A., Kaplan, J., Rozet, J.-M. Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone-rod dystrophy. Europ. J. Hum. Genet. 14: 1269-1273, 2006. [PubMed: 16896346] [Full Text: https://doi.org/10.1038/sj.ejhg.5201691]
Fingert, J. H., Eliason, D. A., Phillips, N. C., Lotery, A. J., Sheffield, V. C., Stone, E. M. Case of Stargardt disease caused by uniparental isodisomy. Arch. Ophthal. 124: 744-745, 2006. [PubMed: 16682602] [Full Text: https://doi.org/10.1001/archopht.124.5.744]
Fishman, G. A., Stone, E. M., Eliason, D. A., Taylor, C. M., Lindeman, M., Derlacki, D. J. ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy. Arch. Ophthal. 121: 851-855, 2003. [PubMed: 12796258] [Full Text: https://doi.org/10.1001/archopht.121.6.851]
Fumagalli, A., Ferrari, M., Soriani, N., Gessi, A., Foglieni, B., Martina, E., Manitto, M. P., Brancato, R., Dean, M., Allikmets, R., Cremonesi, L. Mutational scanning of the ABCR gene with double-gradient denaturing-gradient gel electrophoresis (DG-DGGE) in Italian Stargardt disease patients. Hum. Genet. 109: 326-338, 2001. [PubMed: 11702214] [Full Text: https://doi.org/10.1007/s004390100583]
Gerber, S., Rozet, J. M., van de Pol, T. J. R., Hoyng, C. B., Munnich, A., Blankenagel, A., Kaplan, J., Cremers, F. P. M. Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease. Genomics 48: 139-142, 1998. [PubMed: 9503029] [Full Text: https://doi.org/10.1006/geno.1997.5164]
Gross, M. B. Personal Communication. Baltimore, Md. 6/25/2014.
Guymer, R. H., Heon, E., Lotery, A. J., Munier, F. L., Schorderet, D. F., Baird, P. N., McNeil, R. J., Haines, H., Sheffield, V. C., Stone, E. M. Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch. Ophthal. 119: 745-751, 2001. [PubMed: 11346402] [Full Text: https://doi.org/10.1001/archopht.119.5.745]
Hiller, M., Huse, K., Szafranski, K., Jahn, N., Hampe, J., Schreiber, S., Backofen, R., Platzer, M. Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity. Nature Genet. 36: 1255-1257, 2004. Note: Erratum: Nature Genet. 37: 106 only, 2005. [PubMed: 15516930] [Full Text: https://doi.org/10.1038/ng1469]
Hiller, M., Huse, K., Szafranski, K., Jahn, N., Hampe, J., Schreiber, S., Backofen, R., Platzer, M. Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing. Am. J. Hum. Genet. 78: 291-302, 2006. [PubMed: 16400609] [Full Text: https://doi.org/10.1086/500151]
Kitiratschky, V. B. D., Grau, T., Bernd, A., Zrenner, E., Jagle, H., Renner, A. B., Kellner, U., Rudolph, G., Jacobson, S. G., Cideciyan, A. V., Schaich, S., Kohl, S., Wissinger, B. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. Europ. J. Hum. Genet. 16: 812-819, 2008. [PubMed: 18285826] [Full Text: https://doi.org/10.1038/ejhg.2008.23]
Klevering, B. J., Maugeri, A., Wagner, A., Go, S. L., Vink, C., Cremers, F. P. M., Hoyng, C. B. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology 111: 546-553, 2004. [PubMed: 15019334] [Full Text: https://doi.org/10.1016/j.ophtha.2003.06.010]
Korschen, H. G., Beyermann, M., Muller, F., Heck, M., Vantler, M., Koch, K.-W., Kellner, R., Wolfrum, U., Bode, C., Hofmann, K. P., Kaupp, U. B. Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors. Nature 400: 761-766, 1999. [PubMed: 10466724] [Full Text: https://doi.org/10.1038/23468]
Lee, W., Paavo, M., Zernant, J., Strong, N., Laurente, Z., Bearelly, S., Nagasaki, T., Tsang, S. H., Goldstein, D. B., Allikmets, R. Modification of the PROM1 disease phenotype by a mutation in ABCA4. Ophthalmic Genet. 40: 369-375, 2019. [PubMed: 31576780] [Full Text: https://doi.org/10.1080/13816810.2019.1660382]
Lee, W., Zernant, J., Nagasaki, T., Molday, L. L., Su, P.-I., Fishman, G. A., Tsang, S. H., Molday, R. S., Allikmets, R. Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease. Hum. Molec. Genet. 30: 1293-1304, 2021. [PubMed: 33909047] [Full Text: https://doi.org/10.1093/hmg/ddab122]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
Lewis, R. A., Shroyer, N. F., Singh, N., Allikmets, R., Hutchinson, A., Li, Y., Lupski, J. R., Leppert, M., Dean, M. Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am. J. Hum. Genet. 64: 422-434, 1999. [PubMed: 9973280] [Full Text: https://doi.org/10.1086/302251]
Martinez-Mir, A., Bayes, M., Vilageliu, L., Grinberg, D., Ayuso, C., del Rio, T., Garcia-Sandoval, B., Bussaglia, E., Baiget, M., Gonzalez-Duarte, R., Balcells, S. A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21. Genomics 40: 142-146, 1997. [PubMed: 9070931] [Full Text: https://doi.org/10.1006/geno.1996.4528]
Martinez-Mir, A., Paloma, E., Allikmets, R., Ayuso, C., del Rio, T., Dean, M., Vilageliu, L., Gonzalez-Duarte, R., Balcells, S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. (Letter) Nature Genet. 18: 11-12, 1998. [PubMed: 9425888] [Full Text: https://doi.org/10.1038/ng0198-11]
Maugeri, A., Flothmann, K., Hemmrich, N., Ingvast, S., Jorge, P., Paloma, E., Patel, R., Rozet, J.-M., Tammur, J., Testa, F., Balcells, S., Bird, A. C., and 16 others. The ABCA4 2588G-C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe. Europ. J. Hum. Genet. 10: 197-203, 2002. [PubMed: 11973624] [Full Text: https://doi.org/10.1038/sj.ejhg.5200784]
Maugeri, A., Klevering, B. J., Rohrschneider, K., Blankenagel, A., Brunner, H. G., Deutman, A. F., Hoyng, C. B., Cremers, F. P. M. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am. J. Hum. Genet. 67: 960-966, 2000. [PubMed: 10958761] [Full Text: https://doi.org/10.1086/303079]
Maugeri, A., van Driel, M. A., van de Pol, D. J. R., Klevering, B. J., van Haren, F. J. J., Tijmes, N., Bergen, A. A. B., Rohrschneider, K., Blankenagel, A., Pinckers, A. J. L. G., Dahl, N., Brunner, H. G., Deutman, A. F., Hoyng, C. B., Cremers, F. P. M. The 2588G-C mutation in the ABCR gene is a mild frequent founder mutation in the western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am. J. Hum. Genet. 64: 1024-1035, 1999. [PubMed: 10090887] [Full Text: https://doi.org/10.1086/302323]
Molday, L. L., Rabin, A. R., Molday, R. S. ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy. Nature Genet. 25: 257-258, 2000. [PubMed: 10888868] [Full Text: https://doi.org/10.1038/77004]
Nasonkin, I., Illing, M., Koehler, M. R., Schmid, M., Molday, R. S., Weber, B. H. F. Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease. Hum. Genet. 102: 21-26, 1998. [PubMed: 9490294] [Full Text: https://doi.org/10.1007/s004390050649]
Paloma, E., Martinez-Mir, A., Vilageliu, L., Gonzalez-Duarte, R., Balcells, S. Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies. Hum. Mutat. 17: 504-510, 2001. [PubMed: 11385708] [Full Text: https://doi.org/10.1002/humu.1133]
Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., Travis, G. H. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc. Nat. Acad. Sci. 100: 4742-4747, 2003. [PubMed: 12671074] [Full Text: https://doi.org/10.1073/pnas.0737855100]
Rivera, A., White, K., Stohr, H., Steiner, K., Hemmrich, N., Grimm, T., Jurklies, B., Lorenz, B., Scholl, H. P. N., Apfelstedt-Sylla, E., Weber, B. H. F. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am. J. Hum. Genet. 67: 800-813, 2000. [PubMed: 10958763] [Full Text: https://doi.org/10.1086/303090]
Rozet, J.-M., Gerber, S., Ghazi, I. Perrault, I., Ducroq, D., Souied, E., Cabot, A., Dufier, J.-L., Munnich, A., Kaplan, J. Mutations of the retinal specific ATP binding transporter gene (ABCR) in a single family segregating both autosomal recessive retinitis pigmentosa RP19 and Stargardt disease: evidence of clinical heterogeneity at this locus. J. Med. Genet. 36: 447-451, 1999. [PubMed: 10874631]
Rozet, J.-M., Gerber, S., Souied, E., Perrault, I., Chatelin, S., Ghazi, I., Leowski, C., Dufier, J.-L., Munnich, A., Kaplan, J. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Europ. J. Hum. Genet. 6: 291-295, 1998. Note: Erratum: Europ. J. Hum. Genet. 7: 102 only, 1999. [PubMed: 9781034] [Full Text: https://doi.org/10.1038/sj.ejhg.5200221]
Runhart, E. H., Valkenburg, D., Cornelis, S. S., Khan, M., Santermano, R., Albert, S., Bax, N. M., Astuti, G. D. N., Gilissen C., Pott, J. R., Verheij, J. B. G. M., Blokland, E. A. W., Cremers, F. P. M., van den Born, L. I., Hoyng, C. B. Late-onset Stargardt disease due to mild, deep-intronic ABCA4 alleles. Invest. Ophthal. Vis. Sci. 60: 4249-4256, 2019. [PubMed: 31618761] [Full Text: https://doi.org/10.1167/iovs.19-27524]
Shroyer, N. F., Lewis, R. A., Allikmets, R., Singh, N., Dean, M., Leppert, M., Lupski, J. R. The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial. Vision Res. 39: 2537-2544, 1999. [PubMed: 10396622] [Full Text: https://doi.org/10.1016/s0042-6989(99)00037-1]
Shroyer, N. F., Lewis, R. A., Lupski, J. R. Complex inheritance of ABCR mutations in Stargardt disease: linkage disequilibrium, complex alleles, and pseudodominance. Hum. Genet. 106: 244-248, 2000. [PubMed: 10746567] [Full Text: https://doi.org/10.1007/s004390051034]
Shroyer, N. F., Lewis, R. A., Yatsenko, A. N., Wensel, T. G., Lupski, J. R. Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum. Molec. Genet. 10: 2671-2678, 2001. [PubMed: 11726554] [Full Text: https://doi.org/10.1093/hmg/10.23.2671]
Sieving, P. A., Chaudhry, P., Kondo, M., Provenzano, M., Wu, D., Carlson, T. J., Bush, R. A., Thompson, D. A. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc. Nat. Acad. Sci. 98: 1835-1840, 2001. [PubMed: 11172037] [Full Text: https://doi.org/10.1073/pnas.98.4.1835]
Singh, H. P., Jalali, S., Hejtmancik, J. F., Kannabiran, C. Homozygous null mutations in the ABCA4 gene in two families with autosomal recessive retinal dystrophy. Am. J. Ophthal. 141: 906-913, 2006. [PubMed: 16546111] [Full Text: https://doi.org/10.1016/j.ajo.2005.12.009]
Stenirri, S., Fermo, I., Battistella, S., Galbiati, S., Soriani, N., Paroni, R., Manitto, M. P., Martina, E., Brancato, R., Allikmets, R., Ferrari, M., Cremonesi, L. Denaturing HPLC profiling of the ABCA4 gene for reliable detection of allelic variations. Clin. Chem. 50: 1336-1343, 2004. [PubMed: 15192030] [Full Text: https://doi.org/10.1373/clinchem.2004.033241]
Suarez, T., Biswas, S. B., Biswas, E. E. Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. J. Biol. Chem. 277: 21759-21767, 2002. [PubMed: 11919200] [Full Text: https://doi.org/10.1074/jbc.M202053200]
Sun, H., Molday, R. S., Nathans, J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J. Biol. Chem. 274: 8269-8281, 1999. [PubMed: 10075733] [Full Text: https://doi.org/10.1074/jbc.274.12.8269]
Sun, H., Nathans, J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. (Letter) Nature Genet. 17: 15-16, 1997. [PubMed: 9288089] [Full Text: https://doi.org/10.1038/ng0997-15]
Sun, H., Smallwood, P. M., Nathans, J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nature Genet. 26: 242-246, 2000. [PubMed: 11017087] [Full Text: https://doi.org/10.1038/79994]
Valverde, D., Riveiro-Alvarez, R., Aguirre-Lamban, J., Baiget, M., Carballo, M., Antinolo, G., Millan, J. M., Sandoval, B. G., Ayuso, C. Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest. Ophthal. Vis. Sci. 48: 985-990, 2007. [PubMed: 17325136] [Full Text: https://doi.org/10.1167/iovs.06-0307]
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., Travis, G. H. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98: 13-23, 1999. [PubMed: 10412977] [Full Text: https://doi.org/10.1016/S0092-8674(00)80602-9]
Wiszniewski, W., Zaremba, C. M., Yatsenko, A. N., Jamrich, M., Wensel, T. G., Lewis, R. A., Lupski, J. R. ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum. Molec. Genet. 14: 2769-2778, 2005. [PubMed: 16103129] [Full Text: https://doi.org/10.1093/hmg/ddi310]
Yatsenko, A. N., Shroyer, N. F., Lewis, R. A., Lupski, J. R. Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Hum. Genet. 108: 346-355, 2001. [PubMed: 11379881] [Full Text: https://doi.org/10.1007/s004390100493]