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Mutations in ABCR (ABCA4) in Patients with Stargardt Macular Degeneration or Cone-Rod Degeneration

¹ From the Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Boston; the ² Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida; ³ Schepens Retina Associates, Boston, Massachusetts; and the ⁴ Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

	Abstract

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PURPOSE. To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone–rod degeneration (CRD).

METHODS. One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified.

RESULTS. The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes.

CONCLUSIONS. This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

	Introduction

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Stargardt macular degeneration is characterized by the onset of central vision loss, usually by 20 years of age, progressive bilateral atrophy of the retinal pigment epithelium in the macula, accumulation of a lipofuscin-like substance in the retinal pigment epithelium, and a reduced foveal cone ERG.^{1 2 3 4} It is recessively inherited and has an incidence of approximately 1 in 10,000. Mutations in the ABCR gene, located within chromosome 1p13, have been identified as a cause of recessive Stargardt macular degeneration.^{5 6 7 8} Fundus flavimaculatus is allelic and is regarded by some as the same disorder with a later onset of symptoms and slower progression.^{3 6 9 10 11} Unidentified loci linked to dominant forms of juvenile macular degeneration have been mapped to chromosomes, 6q11-14 (STGD3) and 4p (STGD4).^{12 13 14}

Recessive mutations in ABCR have been found in patients with Stargardt macular degeneration, fundus flavimaculatus, cone–rod degeneration (CRD; a panretinal photoreceptor degeneration with predominant loss of cone function that affects the macula early in its course) and retinitis pigmentosa (a panretinal photoreceptor degeneration usually associated with intraretinal pigmentary deposits).^{5 15 16 17 18 19 20 21 22 23} To date, approximately 200 mutations in ABCR have been found in patients with these diseases.

We report the results from an analysis of ABCR in 118 patients with juvenile macular degeneration and 8 with CRD.

	Materials and Methods

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Ascertainment of Patients
The methods used in this study conformed to the tenets of the Declaration of Helsinki and received approval from the Institutional Review Boards at the Massachusetts Eye and Ear Infirmary and Harvard Medical School. Informed consent was obtained from all patients and family members who participated in the study. Patients with Stargardt macular degeneration were recruited from the Berman-Gund Laboratory (83 patients) and the Bascom Palmer Eye Institute (35 patients). All patients with Stargardt macular degeneration had unaffected parents by history or clinical evaluation. All had reduced central visual acuity before age 30 and characteristic fundus changes of Stargardt macular degeneration. In addition, all patients had diagnostic fluorescein angiograms and/or ERGs consistent with the diagnosis of Stargardt macular degeneration. ERGs showed full-field rod responses that were normal and full-field cone responses that were either normal or slightly reduced and delayed. Foveal ERGs were abnormal in every patient in whom they were measured. Fluorescein angiography revealed a dark choroid in those patients so evaluated.

We also included eight patients with CRD in this mutation screen (five from the Berman-Gund Laboratory, two from the Bascom Palmer Eye Institute, and one from Schepens Retina Associates). Patients with CRD had unaffected parents. Ophthalmoscopy revealed panretinal degeneration affecting the macula more severely. Patients had severely reduced full-field cone ERG amplitudes (reduced 90% or more), moderately reduced cone–rod ERG amplitudes (reduced approximately 50% or more), and markedly delayed cone implicit times (40 msec; normal, 32 msec). Mixed cone–rod responses were typically 30 times larger than cone-isolated responses in young patients with this condition.

Venous blood samples were obtained from participating patients and some of their relatives after informed consent was received. Leukocyte DNA was purified according to standard methods.

Detection of Sequence Changes
DNA samples were screened with the single-strand conformation polymorphism (SSCP) technique for sequence changes in the 50 exons of ABCR (primer sequences are available at a Web site provided by the Massachusetts Eye and Ear Infirmary http://eyegene.meei.harvard.edu/OMGI/ABCR/primers.html). Each exon and 6 to 100 bp of flanking intron sequence were amplified from 20 ng of leukocyte DNA in 20 µl of a solution containing 20 µM dATP, dTTP, and dGTP; 2 µM dCTP, including 0.6 µCi [-³²P]-dCTP (3000 Ci/mmol); 20 mM tris hydrochloride (pH 8.4 or 8.6); 0.25 to 5.0 mM MgCl₂; 50 mM KCl; 0.1 mg/ml bovine serum albumin; 20 pmol of each primer; 0.25 U Taq polymerase; and 0% or 10% dimethyl sulfoxide (DMSO). Conditions for the amplification of each exon were optimized for [MgCl₂], 0% or 10% DMSO, annealing temperature, and pH. In some cases, primer sets for two amplicons with a difference in size of at least 50 bp were combined in the same amplification reaction mixture. Samples were heated to 95°C for 4.5 minutes and incubated for 22 to 27 cycles of the following temperature sequence: 30 seconds at 94°C, 30 seconds at 52°C to 60°C, and 40 seconds at 72°C. Samples underwent a final incubation at 72°C for 5 minutes. After amplification, samples were diluted 1:1 with a solution of 40% formamide, 5 mM EDTA, 0.05% SDS, 0.25% bromphenol blue, 0.25% xylene cyanol, and 0.5x TBE (45 mM Tris-base, 45 mM boric acid, 1 mM disodium EDTA, pH 8.3). The amplified DNA was heat denatured (95°C for 3 minutes), and the resultant single-stranded fragments were separated by gel electrophoresis through 6% polyacrylamide TBE gels, with or without 10% glycerol or through a 5% polyacrylamide gel with TME (30 mM tris, 35 mM 2-[N-morpholino]ethanesulfonic acid, and 1 mM EDTA)²⁴ at 8 to 16 W for 8 to 16 hours. Gels were transferred to Whatman paper (Whatman, Inc., Clifton, NJ), dried, and analyzed by autoradiography. DNA fragments that migrated at rates different from wild-type fragments were evaluated by direct genomic sequencing, according to standard methods.

Individuals without a history of retinal degeneration or blood relatives without retinal degeneration were used as control subjects. Normal control subjects were screened for every likely pathogenic sequence change found in at least 6 of the 126 patients screened.

Neutral and intron sequence changes not affecting the canonical splice-acceptor or splice-donor sites were analyzed for their likelihood of creating or destroying splice sites, by using the neural network software that is available at a Web site provided by the Berkeley Drosophila Genome Project, University of California, Berkeley (www.fruitfly.org/seq_tools/splice.html).²⁵

	Results

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Sequence Changes Identified
On analyzing 118 patients with Stargardt macular degeneration and 8 with CRD, we identified a total of 118 sequence changes (Table 1) , 77 of which were likely to be pathogenic (Fig. 1) . Forty-two of these 77 likely pathogenic sequence changes have not been previously reported. Twenty-one of the changes (including 15 novel changes) were interpreted as obviously null mutations: One was a missense change affecting the initiation codon (Met1Val), four were nonsense mutations, four changed canonical splice-site donor or acceptor sites, and 12 were frameshifts caused by the insertion or deletion of one or more base pairs (Table 1) . We have categorized the splice-site mutation IVS13+2TC as a likely null mutation, although it may only reduce splice donor function because the dinucleotide GC is occasionally found as a splice donor in some genes.

View larger version (22K): [in this window] [in a new window]   Figure 1. Distribution of 77 ABCR mutations found in our patients. Numbers immediately above the bar indicate each exon number. Numbers within the boxes of the bar indicate the number of codons per exon. Numbers below the bar indicate the codon number at exon boundaries.

A rarely encountered missense change, Ala1637Thr, was interpreted as nonpathogenic because it was found in a patient (032-066) who also had two obviously null mutations determined to be allelic by segregation analysis, Lys356Ter and Gln1513(insC). Another change, Ala1038Val, was found in two patients (032-023 and 034-035), and in both cases segregation analysis showed that it was in cis with Leu541Pro, a combination also reported by Rivera et al.²³ We interpreted Leu541Pro as pathogenic because it was found without the Ala1038Val change more frequently in patients than in control subjects. However, Sun et al.²⁶ have shown abnormal ABCR function associated with either Ala1038Val or Leu541Pro, and it is therefore possible that both these changes are pathogenic in isolation. The remaining 49 missense changes were each found in five or fewer patients with Stargardt-CRD and were categorized as likely to be pathogenic. In all, 26 of the 55 likely pathogenic missense changes were novel.

We detected 35 isocoding substitutions and intron changes. These were all interpreted as nonpathogenic. Only one of these, Val2244Val, was predicted to possibly change a splice site. This sequence change affects the first codon of exon 49. Splice-site prediction software identifies the expected splice-acceptor site at the end of intron 48 in the wild-type sequence (probability score 0.98). This changes to a predicted splice-donor site in the mutant sequence (probability score 0.70). Despite this computer-based prediction of an effect on intron splicing, the Val2244Val change was interpreted as nonpathogenic because one of the two patients who were heterozygous for this change (032-066) also had two obvious null mutations determined to be allelic by segregation analysis.

Likely Pathogenic Sequence Changes Found in 95 of 126 Patients
Forty-nine patients with Stargardt and three with CRD had at least two likely pathogenic sequence changes. An additional three with Stargardt and two with CRD were homozygotes for a likely pathogenic sequence change (Leu244Pro, Pro1380Leu, Arg1640Gln, Cys2150Tyr, or Val1973[delG]). We conducted segregation analyses in 20 of these 57 patients’ families, and the results showed that the identified sequence changes segregated as expected for pathogenic alleles (Fig. 2) .

View larger version (40K): [in this window] [in a new window]   Figure 2. Pedigrees of 20 patients in whom segregation analysis was conducted. Arrows: index cases. The ABCR alleles are indicated beneath or to the side of the symbol for each family member whose DNA was evaluated. The clinical findings of the three affected siblings in the family of the proband 032-030 with the R1640Q mutation have been previously reported.33

Thirty-seven patients with Stargardt disease and one with CRD each had only one detectable sequence change that we categorized as likely to be pathogenic. There were a total of 24 unique sequence changes among these 38 patients. Five were null mutations, one was an in-frame deletion, and 18 were missense changes. Eight of the missense changes were found in at least one other index patient who was a compound heterozygote with another likely pathogenic sequence change. Of the remaining 10 missense changes, 8 affect amino acid residues that are identical in the mouse abc1²⁹ and human ABCR proteins (Table 2) . Four of these missense changes also occur in consensus sequences for functional motifs (Table 2) .

Nucleotide 2588G C (Gly863Ala) and Nucleotide 2828GA (Arg943Gln)
One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Maugeri et al.²¹ also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. In our study, the Arg943Gln change was present in five other patients without Gly863Ala, and it was present without Gly863Ala in 9 of 190 control alleles. In addition, a recently reported evaluation of the Gly863Ala mutant protein has shown that it has abnormal function in vitro.²⁶ Taken together, these results indicate that Gly863Ala by itself is likely to be pathogenic and Arg943Gln by itself is not.

Seven of the nine patients with Stargardt disease who were carrying Gly863Ala heterozygously also carried another missense change. Segregation analysis was conducted in the families of four of these 7 patients and the results in all four indicated that the two changes were allelic. Two patients who were heterozygous for the Gly863Ala allele had no other detectable changes likely to be pathogenic.

Nullizygosity Associated with Panretinal Degeneration
We found putative null mutations (e.g., frameshifts, nonsense mutations, or intron splice-site alterations) in 26 (10%) of the 252 alleles screened in this study. Eleven of these patients were compound heterozygotes with one null mutation and a second missense mutation. All had Stargardt macular degeneration. Only four had two allelic null mutations and all four of these patients had the diagnosis of CRD. The ERGs recorded from three of these patients (007-014, 035-002, and 032-066 at ages 24, 21, and 19 years, respectively) showed severely reduced cone amplitudes in response to 30-Hz flickering light (0.2, 0.4, and 6.8 µV, respectively; normal, 50 µV) and showed moderately reduced rod-dominated amplitudes in response to single flashes of light (129, 170, and 180 µV, respectively; normal, 350 µV). The fourth patient (032-081) declined evaluation with an ERG. This is in contrast to patients with Stargardt disease who typically have full-field rod and cone ERG amplitudes in the normal or near-normal range at comparable ages.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We report 118 ABCR sequence changes, including 77 categorized as pathogenic. The 77 likely pathogenic changes include 21 null mutations (15 novel), 55 missense mutations (26 novel), and one novel deletion of a consensus glycosylation site. Of the 236 mutant alleles in the 118 patients with Stargardt macular degeneration, we found mutations in 141 (assuming that all patients with two likely pathogenic mutations were compound heterozygotes). The percentage of Stargardt alleles with an identified ABCR mutation (60%) is comparable to that found in another survey of a large group of patients: Lewis et al.²⁰ found mutations in 57% of the 300 alleles in a set of 150 unrelated subjects.

The absence of detected mutations in 29 patients with Stargardt in our survey is not strong evidence for a second recessive Stargardt disease macular degeneration gene besides ABCR. It is more likely that we missed mutations that lie outside the regions of the gene that were screened (e.g., intron sequence far from flanking exons, the promoter region and the 5' and 3' untranslated regions) or that the SSCP mutation screening technique failed to detect some mutations, especially large deletions or insertions that encompass one or both primer sites used for a PCR amplification. Furthermore, we conducted a search for examples of Stargardt macular degeneration not linked to the ABCR locus. Of the 29 index patients with no detected ABCR mutations, only one (032-070) had both an affected sibling who was willing to participate in our research and an informative polymorphism in the ABCR gene. The index patient and the affected sibling had identical ABCR alleles (data not shown). Thus, even in this multiplex family with Stargardt macular degeneration and no identified ABCR mutations, segregation analysis was consistent with ABCR being the disease locus.

The criteria we and others used to classify sequence variants as "likely" to be pathogenic are not perfect. It is possible that some of the likely pathogenic mutations, especially the missense changes, are nonpathogenic. In addition, because segregation analysis was not always possible or was not always informative, some of the patients with two likely pathogenic changes may not be compound heterozygotes but rather may have a complex allele with both changes in cis. Some of the missense mutants previously associated with Stargardt macular degeneration are reported to have abnormal adenosine triphosphatase (ATPase) activity stimulated by all-trans retinal in vitro.²⁶ It is not yet clear whether this assay reliably distinguishes pathogenic missense variants from those that are nonpathogenic.

Of the eight patients carrying Gly863Ala reported by Maugeri et al.,²¹ five were compound heterozygotes with a null mutation affecting the other allele. This led to speculation that the Gly863Ala sequence change is only pathogenic when present in compound heterozygotes who also carried a null allele. However, none of our patients with this change had a detected null allele. Rather, seven had another missense change and two had no other detectable changes likely to be pathogenic.

ABCR mutations have been reported to cause a spectrum of vision disorders including Stargardt macular degeneration, CRD, and atypical retinitis pigmentosa.^{15 16 17 18 19 20 21 27} Maugeri et al.²¹ and others have proposed a model in which two ABCR alleles with severe (null) mutations result in a visual disorder with features that are more severe than typical Stargardt macular degeneration and that they have called atypical retinitis pigmentosa. According to this model, compound heterozygosity for a severe (null) and a moderately severe mutation causes CRD, whereas two moderately severe mutations or a mild and a severe allele together cause Stargardt macular degeneration. Our findings support this model because all four patients with allelic null mutations (035-002, 032-066, 032-081, and 007-014) whom we encountered had CRD, a panretinal degeneration much more severe than typical Stargardt macular degeneration. A fifth patient with CRD (032-030) was homozygous for the missense change Arg1640Gln and a sixth patient (007-009) had the missense change Gly2146Asp and no other sequence changes that we were able to detect. (The two remaining patients with CRD had no detected ABCR mutations.) Although we have determined that all six of these patients have CRD, the late stages of CRD can have fundus features and extinguished ERGs that are indistinguishable from the late stages of retinitis pigmentosa. Therefore, it may be clearer to consider together in one category both CRD and atypical retinitis pigmentosa caused by severe or null ABCR mutations.

	Acknowledgements

 
The authors thank Ileana Cantillo, Terri McGee, and Jennifer McEvoy for technical assistance.

	Footnotes

 
Supported by Grants EY08683 and EY00169 from the National Eye Institute, Bethesda, Maryland; the Foundation Fighting Blindness, Owings Mills, Maryland; The Ruth and Milton Steinbach Fund, New York, New York; the V. Kann Rasmussen Foundation, Boston, Massachusetts; and Research to Prevent Blindness, New York, New York.

Submitted for publication January 3, 2001; revised April 25, 2001; accepted May 25, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 1734 solely to indicate this fact.

Corresponding author: Thaddeus P. Dryja, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. dryja{at}helix.mgh.harvard.edu

	References

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1. Stargardt, K. (1909) Uber familiare, progressive Degeneration in der Makulagegend des Auges Graefes Arch Klin Exp Ophthalmol 71,534-549
2. Hadden, OB, Gass, JD (1976) Fundus flavimaculatus and Stargardt’s disease Am J Ophthalmol 82,527-539[Medline][Order article via Infotrieve]
3. Noble, KG, Carr, RE (1979) Stargardt’s disease and fundus flavimaculatus Arch Ophthalmol 97,1281-1285[Abstract]
4. Sandberg, MA, Jacobson, SG, Berson, EL (1979) Foveal cone electroretinograms in retinitis pigmentosa and juvenile macular degeneration Am J Ophthalmol 88,702-707[Medline][Order article via Infotrieve]
5. Allikmets, R, Singh, N, Sun, H, et al (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy Nat Genet 15,236-246[Medline][Order article via Infotrieve]
6. Kaplan J, Gerber S, Larget-Piet D, et al. A gene for Stargardt’s disease (fundus flavimaculatus) maps to the short arm of chromosome 1 [published correction appears in Nat Genet. 1994;6:214]. Nat Genet. 1993;5:308–311.
7. Anderson, KL, Baird, L, Lewis, RA, et al (1995) A YAC contig encompassing the recessive Stargardt disease gene (STGD) on chromosome 1p Am J Hum Genet 57,1351-1363[Medline][Order article via Infotrieve]
8. Hoyng, CB, Poppelaars, F, van de Pol, TJ, et al (1996) Genetic fine mapping of the gene for recessive Stargardt disease Hum Genet 98,500-504[Medline][Order article via Infotrieve]
9. Franceschetti, A. (1963) Ueber tapeto-retinale Degenerationen in Kindersalter. In: Entwicklung und Fortschitt in der Augenkeilkunde ,107-120 Enke Verlag Stuttgart, Germany.
10. Fishman, GA (1976) Fundus flavimaculatus: a clinical classification Arch Ophthalmol 94,2061-2067[Abstract]
11. Gerber, S, Rozet, JM, Bonneau, D, et al (1995) A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13 Am J Hum Genet 56,396-399[Medline][Order article via Infotrieve]
12. Donoso, LA, Frost, AT, Stone, EM, et al (2001) Autosomal dominant Stargardt-like macular dystrophy Arch Ophthalmol 119,564-570[Abstract/Free Full Text]
13. Stone, EM, Nichols, BE, Kimura, AE, et al (1994) Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q Arch Ophthalmol 112,765-772[Abstract]
14. Kniazeva, M, Chiang, MF, Morgan, B, et al (1999) A new locus for autosomal dominant stargardt-like disease maps to chromosome 4 Am J Hum Genet 64,1394-1399[Medline][Order article via Infotrieve]
15. Cremers, FP, van de Pol, DJ, van Driel, M, et al (1998) Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR Hum Mol Genet 7,355-362[Abstract/Free Full Text]
16. Gerber, S, Rozet, JM, van de Pol, TJ, et al (1998) 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[Medline][Order article via Infotrieve]
17. Martinez-Mir, A, Paloma, E, Allikmets, R, et al (1998) Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR (Letter; Comment) Nat Genet 18,11-12[Medline][Order article via Infotrieve]
18. Rozet, JM, Gerber, S, Souied, E, et al (1998) Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies Eur J Hum Genet 6,291-295[Medline][Order article via Infotrieve]
19. Fishman, GA, Stone, EM, Grover, S, et al (1999) Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene Arch Ophthalmol 117,504-510[Abstract/Free Full Text]
20. Lewis, RA, Shroyer, NF, Singh, N, et al (1999) Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease Am J Hum Genet 64,422-434[Medline][Order article via Infotrieve]
21. Maugeri, A, van Driel, MA, van de Pol, DJ, et al (1999) The 2588GC 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[Medline][Order article via Infotrieve]
22. Maugeri, A, Klevering, BJ, Rohrschneider, K, et al (2000) Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy Am J Hum Genet 67,960-966[Medline][Order article via Infotrieve]
23. Rivera, A, White, K, Stohr, H, et al (2000) 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[Medline][Order article via Infotrieve]
24. Kukita, Y, Tahira, T, Sommer, SS, et al (1997) SSCP analysis of long DNA fragments in low pH gel Hum Mutat 10,400-407[Medline][Order article via Infotrieve]
25. Reese, MG, Eeckman, FH, Kulp, D, et al (1997) Improved splice site detection in Genie J Comput Biol 4,311-323[Medline][Order article via Infotrieve]
26. Sun, H, Smallwood, PM, Nathans, J. (2000) Biochemical defects in ABCR protein variants associated with human retinopathies Nat Genet 26,242-246[Medline][Order article via Infotrieve]
27. Allikmets, R, Shroyer, NF, Singh, N, et al (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration Science 277,1805-1807[Abstract/Free Full Text]
28. Wiggs, J, Nordenskjold, M, Yandell, D, et al (1988) Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene N Engl J Med 318,151-157[Abstract]
29. Luciani, MF, Chimini, G. (1996) The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death EMBO J 15,226-235[Medline][Order article via Infotrieve]
30. Simonelli, F, Testa, F, de Crecchio, G, et al (2000) New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease Invest Ophthalmol Vis Sci 41,892-897[Abstract/Free Full Text]
31. Nasonkin, I, Illing, M, Koehler, MR, et al (1998) 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[Medline][Order article via Infotrieve]
32. Papaioannou, M, Ocaka, L, Bessant, D, et al (2000) An analysis of ABCR mutations in British patients with recessive retinal dystrophies Invest Ophthalmol Vis Sci 41,16-19[Abstract/Free Full Text]
33. Suzuki, R, Hirose, T. (1998) Bull’s-eye macular dystrophy associated with peripheral involvement Ophthalmologica 212,260-267[Medline][Order article via Infotrieve]
34. Luciani, MF, Denizot, F, Savary, S, et al (1994) Cloning of two novel ABC transporters mapping on human chromosome 9 Genomics 21,150-159[Medline][Order article via Infotrieve]
35. Klugbauer, N, Hofmann, F. (1996) Primary structure of a novel ABC transporter with a chromosomal localization on the band encoding the multidrug resistance-associated protein FEBS Lett 391,61-65[Medline][Order article via Infotrieve]

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