ABCMdb

ABCA4 p.Asp2177Asn

ClinVar:	c.6529G>A , p.Asp2177Asn ? , risk factor
Predicted by SNAP2:	A: D (53%), C: D (53%), E: N (78%), F: D (66%), G: N (57%), H: N (53%), I: D (63%), K: N (53%), L: D (66%), M: D (63%), N: D (71%), P: D (53%), Q: N (57%), R: D (53%), S: N (61%), T: N (72%), V: D (75%), W: D (80%), Y: D (63%),
Predicted by PROVEAN:	A: N, C: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Adenosine triphosphate-binding cassette transporte... Ageing Res Rev. 2003 Jan;2(1):11-24. Efferth T
Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases.
Ageing Res Rev. 2003 Jan;2(1):11-24., [PMID:12437993]

Abstract [show]
The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.

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160 The analysis of the two most frequent AMD-associated ABCA4 variants showed an approximately three-fold elevated risk of AMD for the D2177N variant carriers and an approximately five-fold elevated risk for the G1961E variant carriers. Login to comment

[hide] The ABCR gene: a major disease gene in macular and... Mol Genet Metab. 1999 Oct;68(2):310-5. Rozet JM, Gerber S, Souied E, Ducroq D, Perrault I, Ghazi I, Soubrane G, Coscas G, Dufier JL, Munnich A, Kaplan J
The ABCR gene: a major disease gene in macular and peripheral retinal degenerations with onset from early childhood to the elderly.
Mol Genet Metab. 1999 Oct;68(2):310-5., [PMID:10527682]

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57 Two of the mutations identified (D2177N and G1961E) showed significantly different incidence between AMD and controls (14). Login to comment

[hide] ABC A-subfamily transporters: structure, function ... Biochim Biophys Acta. 2006 May;1762(5):510-24. Epub 2006 Feb 28. Kaminski WE, Piehler A, Wenzel JJ
ABC A-subfamily transporters: structure, function and disease.
Biochim Biophys Acta. 2006 May;1762(5):510-24. Epub 2006 Feb 28., [PMID:16540294]

Abstract [show]
ABC transporters constitute a family of evolutionarily highly conserved multispan proteins that mediate the translocation of defined substrates across membrane barriers. Evidence has accumulated during the past years to suggest that a subgroup of 12 structurally related "full-size" transporters, referred to as ABC A-subfamily transporters, mediates the transport of a variety of physiologic lipid compounds. The emerging importance of ABC A-transporters in human disease is reflected by the fact that as yet four members of this protein family (ABCA1, ABCA3, ABCR/ABCA4, ABCA12) have been causatively linked to completely unrelated groups of monogenetic disorders including familial high-density lipoprotein (HDL) deficiency, neonatal surfactant deficiency, degenerative retinopathies and congenital keratinization disorders. Although the biological function of the remaining 8 ABC A-transporters currently awaits clarification, they represent promising candidate genes for a presumably equally heterogenous group of Mendelian diseases associated with perturbed cellular lipid transport. This review summarizes our current knowledge on the role of ABC A-subfamily transporters in physiology and disease and explores clinical entities which may be potentially associated with dysfunctional members of this gene subfamily.

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188 This was supported by the observation that the frequency of two common ABCA4 variants, G1961E and D2177N, in 1200 patients with AMD is significantly higher (3.4%) than that of controls (0.95%) [88]. Login to comment

[hide] The carboxyterminus of the ATP-binding cassette tr... Biochem Biophys Res Commun. 2002 May 3;293(2):759-65. Buechler C, Boettcher A, Bared SM, Probst MC, Schmitz G
The carboxyterminus of the ATP-binding cassette transporter A1 interacts with a beta2-syntrophin/utrophin complex.
Biochem Biophys Res Commun. 2002 May 3;293(2):759-65., [PMID:12054535]

Abstract [show]
Recent work identified ABCA1 as the major regulator of plasma HDL-cholesterol responsible for the removal of excess choline-phospholipids and cholesterol from peripheral cells and tissues. ABCA1 function may depend on the association with heteromeric proteins and to identify these candidates a human liver yeast two-hybrid library was screened with the carboxyterminal 144 amino acids of ABCA1. Beta2-syntrophin was found to interact with ABCA1 and the C-terminal five amino acids of ABCA1 proned to represent a perfect tail for binding to syntrophin PDZ domains. Immunoprecipitation further confirmed the association of ABCA1 and beta2-syntrophin and in addition utrophin, known to couple beta2-syntrophin and its PDZ ligands to the F-actin cytoskeleton, was identified as a constituent of this complex. ABCA1 in the plasmamembrane of human macrophages was found to be partially associated with Lubrol rafts and effluxed choline-phospholipids involve these microdomains. Beta2-syntrophin does not colocalize in these rafts indicating that beta2-syntrophin may participate in the retaining of ABCA1 in cytoplasmic vesicles and for the targeting of ABCA1 to plasmamembrane microdomains when ABCA1 is released from beta2-syntrophin.

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85 (1) R2144X causing the Tangier disease [32]; (2) P2151L rare single nucleotide polymorphism (own unpublished results); (3) F2163S; (5) V2244I associated with low HDL, hypertrophic cardiomyopathy, and disturbed glucose metabolism; (4) 4 bp insertion at nucleotide 6513 causing a premature stop and Tangier disease [20]. Login to comment
86 (6) R2139W; (7) R2149X causing Stargardt`s disease [33]; (8) C2150W, Stargardt`s disease; (9) 11 bp deletion after K2172 associated with age-related macular degeneration; (10) D2177N associated with age-related macular degeneration; (11) 1 bp deletion after F2189 causing age-related macular degeneration [34]; (12) 1 bp insertion at T2237, the cause of Stargardt`s disease. Login to comment

[hide] ABC transporters in ophthalmic disease. Methods Mol Biol. 2010;637:221-30. Westerfeld C
ABC transporters in ophthalmic disease.
Methods Mol Biol. 2010;637:221-30., [PMID:20419437]

Abstract [show]
ABC transporters have been implicated in a variety of human diseases. The ABCR gene and its protein have been linked to Stargardt's disease, fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. The genetic and molecular pathways involved in the pathogenesis of ABCR-related ophthalmic conditions will be explored. Future diagnostic and therapeutic objectives for these diseases will also be discussed.

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95 A 15-center meta-analysis of the published data on the two most common ABCA4 variants, the D2177N and G1961E alleles, found the two variants to be present in 3.4% of patients with AMD in comparison to 0.95% of controls (39). Login to comment

[hide] Outcome of ABCA4 microarray screening in routine c... Mol Vis. 2009 Dec 20;15:2841-7. Ernest PJ, Boon CJ, Klevering BJ, Hoefsloot LH, Hoyng CB
Outcome of ABCA4 microarray screening in routine clinical practice.
Mol Vis. 2009 Dec 20;15:2841-7., [PMID:20029649]

Abstract [show]
PURPOSE: To retrospectively analyze the clinical characteristics of patients who were screened for mutations with the ATP-binding cassette transporter gene ABCA4 (ABCA4) microarray in a routine clinical DNA diagnostics setting. METHODS: We performed a retrospective analysis of the medical charts of 65 patients who underwent an ABCA4 microarray screening between the years 2002 and 2006. An additional denaturing gradient gel electrophoresis (DGGE) was performed in these patients if less than two mutations were found with the microarray. We included all patients who were suspected of autosomal recessive Stargardt disease (STGD1), autosomal recessive cone-rod dystrophy (arCRD), or autosomal recessive retinitis pigmentosa at the time of microarray request. After a retrospective analysis of the clinical characteristics, the patients who were suspected of STGD1 were categorized as having either a typical or atypical form of STGD1, according to the age at onset, fundus appearance, fluorescein angiography, and electroretinography. The occurrence of typical clinical features for STGD1 was compared between patients with different numbers of discovered mutations. RESULTS: Of the 44 patients who were suspected of STGD1, 26 patients (59%) had sufficient data available for a classification in either typical (six patients; 23%) or atypical (20 patients; 77%) STGD1. In the suspected STGD1 group, 59% of all expected pathogenic alleles were found with the ABCA4 microarray. DGGE led to the finding of 12 more mutations, resulting in an overall detection rate of 73%. Thirty-one percent of patients with two or three discovered ABCA4 mutations met all typical STGD1 criteria. An age at onset younger than 25 years and a dark choroid on fluorescein angiography were the most predictive clinical features to find ABCA4 mutations in patients suspected of STGD1. In 18 patients suspected of arCRD, microarray screening detected 22% of the possible pathogenic alleles. CONCLUSIONS: In addition to confirmation of the diagnosis in typical STGD1, ABCA4 microarray screening is usually requested in daily clinical practice to strengthen the diagnosis when the disease is atypical. This study supports the view that the efficiency and accuracy of ABCA4 microarray screening are directly dependent upon the clinical features of the patients who are screened.

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143 DISCOVERED MUTATIONS IN THE ABCA4 GENE IN THE PATIENTS INCLUDED IN THIS STUDY Nucleotide change Effect Alleles References Mutations already included in the ABCA4 microarray c.286A>G p.Asn96Asp 2 [25] c.656G>C p.Arg219Thr 1 [10] c.740A>T p.Asn247Ile 1 This study* c.768G>T splice site 7 [13] c.899C>A p.Thr300Asn 1 [14] c.1805G>A p.Arg602Gln 1 [9] c.1822T>A p.Phe608Ile 2 [13] c.1853G>A p.Gly618Glu 1 [19] c.1938-1G>A splice site 1 [26] c.2588G>C p.DelGly863/Gly863Ala 8 [13] c.2919del exons20-22 deletion/frameshift 2 [13] c.3335C>A p.Thr1112Asn 1 [13] c.3874C>T p.Gln1292X 1 This study* c.3899G>A p.Arg1300Gln 1 [27] c.4297G>A p.Val1433Ile 1 [17] c.4462T>C p.Cys1488Arg 1 [17] c.4506C>A p.Cys1502X 1 This study* c.4539+1G>T splice site 1 [28] c.4774+1G>A splice site 1 [1] c.5161-5162delAC p.Thr1721fs 1 [27] c.5337C>A p.Tyr1779X 1 This study* c.5461-10T>C unknown 9 [9] c.5537T>C p.Ile1846Thr 1 [13] c.5693G>A p.Arg1898His 1 [1] c.5715+5G>A splice site 2 [28] c.5882G>A p.Gly1961Glu 10 [1] c.6088C>T p.Arg2030X 1 [14] c.6089G>A p.Arg2030Gln 1 [9] c.6238-6239delTC p.Ser2080fs 1 [29] c.6529G>A p.Asp2177Asn 1 [1] New mutations found with DGGE analysis c.303+4A>C splice site 1 c.872C>T p.Pro291Leu 1 c.2906A>G p.Lys969Arg 1 c.2947A>G p.Thr983Ala 1 c.3233G>A p.Gly1078Glu 1 c.3305A>T p.Asp1102Val 1 c.4353+1G>A splice site 1 c.5113C>T p.Arg1705Trp 1 c.5762_5763dup p.Ala1922fs 1 c.6411T>A p.Cys2137X 1 Total 74 Mutations are designated by their nucleotide change, followed by their effect on the protein and the number of alleles that were found with the mutation. Login to comment

[hide] Frequency of ABCA4 mutations in 278 Spanish contro... Br J Ophthalmol. 2009 Oct;93(10):1359-64. Epub 2008 Oct 31. Riveiro-Alvarez R, Aguirre-Lamban J, Lopez-Martinez MA, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, Avila-Fernandez A, Ramos C, Ayuso C
Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease.
Br J Ophthalmol. 2009 Oct;93(10):1359-64. Epub 2008 Oct 31., [PMID:18977788]

Abstract [show]
AIM: To determine the carrier frequency of ABCA4 mutations in order to achieve an insight into the prevalence of autosomal recessive Stargardt disease (arSTGD) in the Spanish population. METHODS: arSTGD patients (n = 133) were analysed using ABCR400 microarray and sequencing. Control subjects were analysed by two different strategies: 200 individuals were screened for the p.Arg1129Leu mutation by denaturing-HPLC and sequencing; 78 individuals were tested for variants with the microarray and sequencing. RESULTS: For the first strategy in control subjects, the p.Arg1129Leu variant was found in two heterozygous individuals, which would mean a carrier frequency for any variant of approximately 6.0% and a calculated arSTGD prevalence of 1:1000. For the second strategy, carrier frequency was 6.4% and therefore an estimated prevalence of the disease of 1:870. CONCLUSION: Calculated prevalence of arSTGD based on the ABCA4 carrier frequency could be considerably higher than previous estimation. This discrepancy between observed (genotypic) and estimated (phenotypic) prevalence could be due to the existence of non-pathological or low penetrance alleles, which may result in late-onset arSTGD or may be implicated in age-related macular degeneration. This situation should be regarded with special care when genetic counselling is given and further follow-up of these patients should be recommended.

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96 These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. Login to comment
97 These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. Login to comment

[hide] Stargardt's disease and the ABCR gene. Semin Ophthalmol. 2008 Jan-Feb;23(1):59-65. Westerfeld C, Mukai S
Stargardt's disease and the ABCR gene.
Semin Ophthalmol. 2008 Jan-Feb;23(1):59-65., [PMID:18214793]

Abstract [show]
Stargardt's disease is an autosomal recessive form of juvenile macular degeneration. The clinical presentation, relevant ancillary tests, and classic histologic features will be reviewed. The role of genetic mutations in the pathophysiology of Stargardt's disease will also be explored. Stargardt's disease is caused by mutations in the ABCR (ABCA4) gene on chromosome 1. Mutations in this gene have also been attributed to some cases of cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. The genetic and molecular pathways that produce Stargardt's disease will be discussed. Future diagnostic and therapeutic objectives for this visually disabling condition will also be presented.

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107 In an international 15-center meta-analysis of the published data on the two most common ABCA4 variants, the D2177N and G1961E alleles, there was a statistically significant but small correlation with AMD. Login to comment

[hide] Severe autosomal recessive retinitis pigmentosa ma... Hum Genet. 2005 Dec;118(3-4):356-65. Epub 2005 Sep 28. Zhang Q, Zulfiqar F, Xiao X, Riazuddin SA, Ayyagari R, Sabar F, Caruso R, Sieving PA, Riazuddin S, Hejtmancik JF
Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3-p21.2 between D1S2896 and D1S457 but outside ABCA4.
Hum Genet. 2005 Dec;118(3-4):356-65. Epub 2005 Sep 28., [PMID:16189710]

Abstract [show]
A severe form of autosomal recessive retinitis pigmentosa (arRP) was identified in a large Pakistani family ascertained in the Punjab province of Pakistan. All affected individuals in the family had night blindness in early childhood, early complete loss of useful vision, and typical RP fundus changes plus macular degeneration. After exclusion of known arRP loci, a genome-wide scan was performed using microsatellite markers at about 10 cM intervals and calculating two-point lod scores. PCR cycle dideoxynucleotide sequencing was used to sequence candidate genes inside the linked region for mutations. RP in this family shows linkage to markers in a 10.5 cM (8.9 Mbp) region of chromosome 1p13.3-p21.2 between D1S2896 and D1S457. D1S485 yields the highest lod score of 6.54 at theta=0. Sequencing the exons and intron-exon boundaries of five candidate genes and six ESTs in this region, OLFM3, GNAI3, LOC126987, FLJ25070, DKFZp586G0123, AV729694, BU662869, BU656110, BU171991, BQ953690, and CA397743, did not identify any causative mutations. This novel locus lies approximately 4.9 cM (7.1 Mbp) from ABCA4, which is excluded from the linked region. Identification and study of this gene may help to elucidate the phenotypic diversity of arRP mapping to this region.

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132 However, choroidal atrophy in the posterior pole is much more Table 2 Two-point linkage results for markers in the ARRP region at 1p13.2-p21.2 Markers Position Lod score at h value Zmax hmax cM Mbpa 0.00 0.01 0.05 0.10 0.20 0.30 0.40 D1S2868 129.90 93.05 À¥ À1.96 0.40 1.07 1.19 0.81 0.29 1.24 0.16 D1S236 132.40 93.82 À¥ 1.03 2.07 2.22 1.88 1.27 0.56 2.22 0.10 D1S2664 133.00 95.66 À¥ 2.91 3.81 3.78 3.06 2.01 0.86 3.85 0.07 D1S2793 133.00 96.81 À¥ 3.26 4.14 4.08 3.29 2.17 0.96 4.17 0.07 D1S2808 135.20 98.97 À¥ 2.33 3.25 3.25 2.62 1.70 0.69 3.30 0.07 D1S2671 137.40 100.98 À¥ 3.47 4.34 4.29 3.48 2.34 1.07 4.38 0.07 D1S206 137.60 101.40 À¥ 2.16 2.54 2.44 1.90 1.23 0.52 2.54 0.05 D1S2896 137.30 101.68 À¥ 1.05 2.07 2.21 1.86 1.23 0.53 2.21 0.09 D1S495 140.80 102.27 3.35 4.57 4.76 4.42 3.39 2.17 0.93 4.80 0.03 D1S2699 140.70 104.49 1.52 2.77 3.06 2.86 2.14 1.29 0.46 3.06 0.04 D1S485 140.60 104.98 6.54 6.41 5.89 5.23 3.86 2.46 1.07 6.54 0.00 D1S429 140.50 105.41 3.70 4.90 5.06 4.68 3.56 2.25 0.94 5.11 0.03 D1S2759 140.30 105.56 3.70 5.25 5.41 5.01 3.85 2.49 1.09 5.46 0.03 D1S239 143.10 106.55 0.04 1.27 1.70 1.67 1.31 0.82 0.31 1.71 0.07 D1S248 143.30 106.87 3.41 4.63 4.82 4.48 3.45 2.23 0.97 4.85 0.04 D1S457 147.80 110.59 À¥ À4.63 À1.44 À0.30 0.42 0.45 0.20 0.74 0.80 D1S2726 149.00 110.90 À¥ À3.52 À0.47 0.51 0.97 0.81 0.41 0.97 0.21 a Build 35.1 (9-15-04) Table 3 Haplotypes of four affected individuals in the pedigree using the sequence changes in the ABCA4 gene Exon Nucleotide change Amino acid change Individual number 9 17 27 30 10 1268 A>G H423R A/A A/A A/A G/A 1269 C>T H423H T/T T/T C/C C/C delG IVS+5 Splice G/G G/G G/T G/T 19 2828 G>A R943Q A/A A/A G/G G/G 33 IVS+48 C>T Splice C/C C/C T/T C/T 45 6249 C>T I2083I C/C C/C T/C C/C 46 6285 T>C D2095D T/T T/T C/T T/T 48 6529 G>A D2177N G/G G/G G/G A/G 49 6764 G>T S2255I G/G G/G T/G G/G Italic-wild-type alleles; underlined-nucleotide substitutions which do not lead to the amino acid substitution and/or common polymorphisms; bold-nucleotide substitution which results in an amino acid substitution; the individual numbers in Table 3 are consistent with those in Figs. Login to comment
131 However, choroidal atrophy in the posterior pole is much more Table 2 Two-point linkage results for markers in the ARRP region at 1p13.2-p21.2 Markers Position Lod score at h value Zmax hmax cM Mbpa 0.00 0.01 0.05 0.10 0.20 0.30 0.40 D1S2868 129.90 93.05 &#a5; 1.96 0.40 1.07 1.19 0.81 0.29 1.24 0.16 D1S236 132.40 93.82 &#a5; 1.03 2.07 2.22 1.88 1.27 0.56 2.22 0.10 D1S2664 133.00 95.66 &#a5; 2.91 3.81 3.78 3.06 2.01 0.86 3.85 0.07 D1S2793 133.00 96.81 &#a5; 3.26 4.14 4.08 3.29 2.17 0.96 4.17 0.07 D1S2808 135.20 98.97 &#a5; 2.33 3.25 3.25 2.62 1.70 0.69 3.30 0.07 D1S2671 137.40 100.98 &#a5; 3.47 4.34 4.29 3.48 2.34 1.07 4.38 0.07 D1S206 137.60 101.40 &#a5; 2.16 2.54 2.44 1.90 1.23 0.52 2.54 0.05 D1S2896 137.30 101.68 &#a5; 1.05 2.07 2.21 1.86 1.23 0.53 2.21 0.09 D1S495 140.80 102.27 3.35 4.57 4.76 4.42 3.39 2.17 0.93 4.80 0.03 D1S2699 140.70 104.49 1.52 2.77 3.06 2.86 2.14 1.29 0.46 3.06 0.04 D1S485 140.60 104.98 6.54 6.41 5.89 5.23 3.86 2.46 1.07 6.54 0.00 D1S429 140.50 105.41 3.70 4.90 5.06 4.68 3.56 2.25 0.94 5.11 0.03 D1S2759 140.30 105.56 3.70 5.25 5.41 5.01 3.85 2.49 1.09 5.46 0.03 D1S239 143.10 106.55 0.04 1.27 1.70 1.67 1.31 0.82 0.31 1.71 0.07 D1S248 143.30 106.87 3.41 4.63 4.82 4.48 3.45 2.23 0.97 4.85 0.04 D1S457 147.80 110.59 &#a5; 4.63 1.44 0.30 0.42 0.45 0.20 0.74 0.80 D1S2726 149.00 110.90 &#a5; 3.52 0.47 0.51 0.97 0.81 0.41 0.97 0.21 a Build 35.1 (9-15-04) Table 3 Haplotypes of four affected individuals in the pedigree using the sequence changes in the ABCA4 gene Exon Nucleotide change Amino acid change Individual number 9 17 27 30 10 1268 A>G H423R A/A A/A A/A G/A 1269 C>T H423H T/T T/T C/C C/C delG IVS+5 Splice G/G G/G G/T G/T 19 2828 G>A R943Q A/A A/A G/G G/G 33 IVS+48 C>T Splice C/C C/C T/T C/T 45 6249 C>T I2083I C/C C/C T/C C/C 46 6285 T>C D2095D T/T T/T C/T T/T 48 6529 G>A D2177N G/G G/G G/G A/G 49 6764 G>T S2255I G/G G/G T/G G/G Italic-wild-type alleles; underlined-nucleotide substitutions which do not lead to the amino acid substitution and/or common polymorphisms; bold-nucleotide substitution which results in an amino acid substitution; the individual numbers in Table 3 are consistent with those in Figs. 1 and 2 and Table 1 obvious in the two families with ABCA4 mutations (Cremers et al. 1998; Klevering et al. 1999; Martinez-Mir et al. 1997, 1998). Login to comment

[hide] ABCA4 mutations causing mislocalization are found ... Hum Mol Genet. 2005 Oct 1;14(19):2769-78. Epub 2005 Aug 15. Wiszniewski W, Zaremba CM, Yatsenko AN, Jamrich M, Wensel TG, Lewis RA, Lupski JR
ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies.
Hum Mol Genet. 2005 Oct 1;14(19):2769-78. Epub 2005 Aug 15., [PMID:16103129]

Abstract [show]
ABCA4, also called ABCR, is a retinal-specific member of the ATP-binding cassette (ABC) family that functions in photoreceptor outer segments as a flipase of all-trans retinal. Homozygous and compound heterozygous ABCA4 mutations are associated with various autosomal recessive retinal dystrophies, whereas heterozygous ABCA4 mutations have been associated with dominant susceptibility to age-related macular degeneration in both humans and mice. We analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400 in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein. These mutations cause 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 two misfolding alleles exhibit early age-of-onset (AO) (5-12 years) of retinal disease. Our data suggest that a class of ABCA4 mutants may be an important determinant of the AO of disease.

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44 A WT 168-05 24 20/25 OD; 20/30 OS;VF , 308 OU RP N/A N/A 168-06 26 N/A RP N/A N/A AR192 192-03 9 20/20 OD; 20/25 OS;VF , 58 OU RP D2177N WT 192-04 19 20/30 OD; 20/40 OS;VF , 58 OU RP WT WT 192-05 19 20/30 OD; 20/40 OS;VF , 58 OU RP WT WT AR194 194-03 30 N/A RP D2177N WT 194-05 Childhood 20/25 OD; 20/40 OS RP N/A N/A 194-06 5 N/A RP D2177N WT 194-07 4 or 5 20/80 OU RP N/A N/A AR197 197-05 7 CF 3 feet OD; CF 2 feet OS RP [L541P; A1038V] [L541P; A1038V] 197-06 9 CF 5 feet OD; HM OS RP [L541P; A1038V] [L541P; A1038V] AR554 554-03 2 10/12 20/60 OU RP V2050L WT 554-04 1 9/12 N/A RP N/A N/A AR591 591-03 20 20/25 OU RP N/A N/A 591-04 8 20/20 OD; 20/25 OS;VF , 108 OU RP G1961E WT AR689 689-03 7 N/A RP R408X R602W 689-08 7 N/A RP N/A N/A OD, right eye; OS, left eye; OU, both eyes; VF, visual field; RP, retinitis pigementosa, WT, wild type; N/A, not available; CF, counting fingers; HM, hand motions. Login to comment

[hide] Age matters--thoughts on a grading system for ABCA... Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):87-9. Epub 2004 Dec 22. Lorenz B, Preising MN
Age matters--thoughts on a grading system for ABCA4 mutations.
Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):87-9. Epub 2004 Dec 22., [PMID:15614538]

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33 All carry mutations which have been reported mostly in AMD (D2177N, V2050L [1, 16, 18]) or STGD (L541P+A1038V [3]). Login to comment
34 All carry mutations which have been reported mostly in AMD (D2177N, V2050L [1, 16, 18]) or STGD (L541P+A1038V [3]). Login to comment

[hide] The spectrum of retinal phenotypes caused by mutat... Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):90-100. Epub 2004 Dec 22. Klevering BJ, Deutman AF, Maugeri A, Cremers FP, Hoyng CB
The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene.
Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):90-100. Epub 2004 Dec 22., [PMID:15614537]

Abstract [show]
BACKGROUND: The majority of studies on the retina-specific ATP-binding cassette transporter (ABCA4) gene have focussed on molecular genetic analysis; comparatively few studies have described the clinical aspects of ABCA4-associated retinal disorders. In this study, we demonstrate the spectrum of retinal dystrophies associated with ABCA4 gene mutations. METHODS: Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders were selected. All patients received an extensive ophthalmologic evaluation, including kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray (ABCR400 chip) and/or single-strand conformation polymorphism analysis in combination with direct DNA sequencing. RESULTS: In all patients, at least one pathologic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhibited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4-associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phenotype was characterised by extensive atrophy with almost complete loss of peripheral and central retinal functions. CONCLUSION: We describe nine patients during different stages of disease progression; together, these patients form a continuum of ABCA4-associated phenotypes. Besides characteristic disorders such as FFM/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as the disease progresses, marked differences may be observed between initially comparable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patients were compatible with the resulting phenotypes, as predicted by the genotype-phenotype model for ABCA4-associated disorders. With the advent of therapeutic options, recognition by the general ophthalmologist of the various retinal phenotypes associated with ABCA4 mutations is becoming increasingly important.

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156 The assumption that certain heterozygous ABCA4 mutations are associated with AMD is primarily founded on the observation that a three- to fivefold elevated risk of AMD exists for carriers of the D2177N and G1961E variants [2-4]. Login to comment
157 The assumption that certain heterozygous ABCA4 mutations are associated with AMD is primarily founded on the observation that a threeto fivefold elevated risk of AMD exists for carriers of the D2177N and G1961E variants [2-4]. Login to comment

[hide] Evolution of ABCA4 proteins in vertebrates. J Mol Evol. 2005 Jan;60(1):72-80. Yatsenko AN, Wiszniewski W, Zaremba CM, Jamrich M, Lupski JR
Evolution of ABCA4 proteins in vertebrates.
J Mol Evol. 2005 Jan;60(1):72-80., [PMID:15696369]

Abstract [show]
The ABCA4 (ABCR) gene encodes a retinal-specific ATP-binding cassette transporter. Mutations in ABCA4 are responsible for several recessive macular dystrophies and susceptibility to age related macular degeneration (AMD). The protein appears to function as a flippase of all-trans-retinaldehyde and/or its derivatives across the membrane of outer segment disks and is a potentially important element in recycling visual cycle metabolites. However, the understanding of ABCA4's role in the visual cycle is limited due to the lack of a direct functional assay. An evolutionary analysis of ABCA4 may aid in the identification of conserved elements, the preservation of which implies functional importance. To date, only human, murine, and bovine ABCA4 genes are described. We have identified ABCA4 genes from African (Xenopus laevis) and Western (Silurana tropicalis) clawed frogs. A comparative analysis describing the evolutionary relationships between the frog ABCA4s, annotated T. rubripes ABCA4, and mammalian ABCA4 proteins was carried out. Several segments are conserved in both intradiscal loop (IL) domains, in addition to the transmembrane and ATP-binding domains. Nonconserved segments were found in the IL and cytoplasmic linker domains. Maximum likelihood analyses of the aligned sequences strongly suggest that ABCA4 was subject to purifying selection. Collectively, these data corroborate the current evolutionary model where two distinct ABCA half-transporter progenitors were combined to form a full ABCA4 progenitor in ancestral chordates. We speculate that evolutionary alterations may increase the retinoid metabolite recycling capacity of ABCA4 and may improve dark adaptation.

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131 Missense AMD-associated ABCA4 mutations D2177N and I1562T map to nonconserved sites. Login to comment

[hide] Microarray-based mutation analysis of the ABCA4 (A... Eur J Hum Genet. 2004 Dec;12(12):1024-32. Klevering BJ, Yzer S, Rohrschneider K, Zonneveld M, Allikmets R, van den Born LI, Maugeri A, Hoyng CB, Cremers FP
Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.
Eur J Hum Genet. 2004 Dec;12(12):1024-32., [PMID:15494742]

Abstract [show]
Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

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101 Likewise, the known Table 2 ABCA4 sequence variants in RP patients RP patient number Inheritance Allele 1 Allele 2 Nucleotide change Effect Nucleotide change Effect 9304 Aut. Rec. 2588G4C; 2828G4Aa DG863/G863A; R943Q 5888delG R1963fs 9444 Aut. Rec. 6529G4A D2177N Not identified 9545 Isolated 6529G4A D2177N Not identified 14753 Isolated 1622T4C; 3113C4T L541P; A1038V Not identified 17597 Isolated 6148G4C V2050L Not identified a Polymorphic variants 4203A, 5603 T, and 5682C also present. Login to comment
131 In two RP patients, we identified the D2177N mutation heterozygously. Login to comment
132 The D2177N mutation has never been found in patients with STGD1 but was found to be associated with age-related macular degeneration at a statistically significant level.25 As shown by Sun et al,50 this mutation, contrary to other mutations, results in increased ATP hydrolysis when compared to the wild-type protein. Login to comment
133 These data do not allow us to draw a definitive conclusion regarding the pathologic nature of D2177N. Login to comment
143 Given this clinical presentation and the fact that homozygous null mutations were not found Table 5 Functional assessment of missense (A) and splice site (B) mutations (A) Missense mutation Nature of amino-acid change Effect on ABCR functionRef R18W Nonconservative Unknown R24C Nonconservative Unknown; adjacent to first transmembrane domain G65E Nonconservative Unknown E161K Nonconservative Unknown L541P Conservative Decreased ATP binding and ATPase activity50 P597S Nonconservative Unknown G618E Nonconservative Unknown V767D Nonconservative Decreased ABCR expression10 G863A Nonconservative Decreased ATPase activity50, 51 R943Q Nonconservative Decreased ATPase activity51 A1038V Conservative Decreased ATP binding and ATPase activity50 E1087K Nonconservative Decreased ATP binding50 V1433I Conservative Unknown R1640W Nonconservative Unknown A1794D Nonconservative Introduction charged aa in 10th transmembrane domain G1961E Nonconservative Decreased ATP binding and ATPase activity 50 V2050L Conservative Unknown D2177N Nonconservative Increased ATPase activity50 (B) Splice site mutation Effect on mRNARef Predicted effect on ABCR protein 768G4T Nonsense-mediated decay33 No protein IVS36+2T4C Unknown Truncation of exon 36 resulting in V1673fs? Login to comment

[hide] Denaturing HPLC profiling of the ABCA4 gene for re... Clin Chem. 2004 Aug;50(8):1336-43. Epub 2004 Jun 10. Stenirri S, Fermo I, Battistella S, Galbiati S, Soriani N, Paroni R, Manitto MP, 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. 2004 Aug;50(8):1336-43. Epub 2004 Jun 10., [PMID:15192030]

Abstract [show]
BACKGROUND: Mutations in the retina-specific ABC transporter (ABCA4) gene have been associated with several forms of macular degenerations. Because the high complexity of the molecular genotype makes scanning of the ABCA4 gene cumbersome, we describe here the first use of denaturing HPLC (DHPLC) to screen for ABCA4 mutations. METHODS: Temperature conditions were designed for all 50 exons based on effective separation of 83 samples carrying 86 sequence variations and 19 mutagenized controls. For validation, samples from 23 previously characterized Stargardt patients were subjected to DHPLC profiling. Subsequently, samples from a cohort of 30 patients affected by various forms of macular degeneration were subjected to DHPLC scanning under the same conditions. RESULTS: DHPLC profiling not only identified all 132 sequence alterations previously detected by double-gradient denaturing gradient gel electrophoresis but also identified 5 sequence alterations that this approach had missed. Moreover, DHPLC scanning of an additional panel of 30 previously untested patients led to the identification of 26 different mutations and 29 polymorphisms, accounting for 203 sequence variations on 29 of the 30 patients screened. In total, the DHPLC approach allowed us to identify 16 mutations that had never been reported before. CONCLUSIONS: These results provide strong support for the use of DHPLC for molecular characterization of the ABCA4 gene.

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No. Sentence Comment
35 Exon Genotypesa Exon Genotypesa 1b M1V (1A>G) (11) 24 3523-28TϾC (12) R18W (52C>T) (11) 25 G1203D (3608G>A)b 3 250_251insCAAA (7) 27 R1300X (3898C>T) (12) N96K (288C>A) R1300Q (3899G>A) (11) 302 ϩ 26 GϾA (13) 28 P1380L (4139CϾT) (14) 4 P143L (428C>T) (10) P1401P (4203CϾA) (15) 5 R152Q (455G>A) (4) 4253 ϩ 43GϾA (12) 6 571-1GϾT (4) 29 4253 ϩ 13GϾA (12) R212H (635G>A) (16) 4354-38GϾA (4) C230S (688T>A) (12) 30a 4466 ϩ 3GϾA (4) 641delG (9) 30b C1490Y (4469G>A) (17) 10 1240-14CϾT (13) P1512R (4535C>G) (4) H423R (1268ϾG) (13) 31 T1526M (4577C>T) (14) 1357 ϩ 11delG (16) 33/34 A1598D (4793C>A) (4) H423H (1269CϾT) (13) 35 4947delC (14) 11 1387delTT (4) 5018 ؉ 2T>C (7) R500R (1500GϾA) (4) 39 H1838Y (5512C>T) (14) 12 L541P (1622T>C) (14) 40 N1868I (5603AϾT) (13) R572Q (1715G>A) (17) L1894L (5682GϾC) (15) 13 Y639X (1917C>G) (17) 5714 ؉ 5G>A C641S (1922G>C) (4) 41 L1938L (5814AϾG) (12) 14 R653C (1957C>T) (12) 42 5836-43CϾA W700X (2099G>A) (4) 5836-11GϾA (15) 3607 ϩ 49TϾC P1948I (5843CϾT) (15) 15 V767D (2300T>A) (7) P1948P (5844AϾG) (15) 16 W821R (2461T>A) (14) G1961E (5882G>A) (14) 17 2588-33CϾTb 43 L1970F (5908C>T) (11) G863A (2588G>C) (17) 44 6006-16AϾG (16) 18 2654-36CϾT (4) I2023I (6069CϾT) (14) T897I (2690C>T) (7) L2027F (6079C>T) (14) 19 R943Q (2828GϾA) (13) 45 V2050L (6148G>C) (14) Y954D (2860T>G) (4) 46 R2107H (6320G>A) (18) N965S (2894A>G) (14) 6386 ؉ 2G>C (10) 20 G978D (2933G>A) (4) 47 R2139W (6415C>T) (14) L988L (2964CϾT) (4) R2149L (6446G>T) (4) 21 E1022K (3064G>A) (4) C2150Y (6449G>A) (19) A1038V (3113C>T) (14) 48 D2177N (6529G>A) (17) G1050D (3149G>A) (4) L2241V (6721C>G) (12) 3211_3212insGT (14) 6729 ϩ 21CϾT (15) 22 E1087K (3259G>A) (14) 49 6730-3TϾC (15) R1098C (3292C>T) (12) S2255I (6764GϾT) (13) S1099P (3295T>C) (4) 6816 ϩ 28GϾC (4) R1108C (3322C>T) (14) R1129L (3386G>T) (17) a Bold indicates disease-causing mutations. Login to comment
34 Exon Genotypesa Exon Genotypesa 1b M1V (1A>G) (11) 24 3523-28Tb0e;C (12) R18W (52C>T) (11) 25 G1203D (3608G>A)b 3 250_251insCAAA (7) 27 R1300X (3898C>T) (12) N96K (288C>A) R1300Q (3899G>A) (11) 302 af9; 26 Gb0e;A (13) 28 P1380L (4139Cb0e;T) (14) 4 P143L (428C>T) (10) P1401P (4203Cb0e;A) (15) 5 R152Q (455G>A) (4) 4253 af9; 43Gb0e;A (12) 6 571-1Gb0e;T (4) 29 4253 af9; 13Gb0e;A (12) R212H (635G>A) (16) 4354-38Gb0e;A (4) C230S (688T>A) (12) 30a 4466 af9; 3Gb0e;A (4) 641delG (9) 30b C1490Y (4469G>A) (17) 10 1240-14Cb0e;T (13) P1512R (4535C>G) (4) H423R (1268b0e;G) (13) 31 T1526M (4577C>T) (14) 1357 af9; 11delG (16) 33/34 A1598D (4793C>A) (4) H423H (1269Cb0e;T) (13) 35 4947delC (14) 11 1387delTT (4) 5018 d19; 2T>C (7) R500R (1500Gb0e;A) (4) 39 H1838Y (5512C>T) (14) 12 L541P (1622T>C) (14) 40 N1868I (5603Ab0e;T) (13) R572Q (1715G>A) (17) L1894L (5682Gb0e;C) (15) 13 Y639X (1917C>G) (17) 5714 d19; 5G>A C641S (1922G>C) (4) 41 L1938L (5814Ab0e;G) (12) 14 R653C (1957C>T) (12) 42 5836-43Cb0e;A W700X (2099G>A) (4) 5836-11Gb0e;A (15) 3607 af9; 49Tb0e;C P1948I (5843Cb0e;T) (15) 15 V767D (2300T>A) (7) P1948P (5844Ab0e;G) (15) 16 W821R (2461T>A) (14) G1961E (5882G>A) (14) 17 2588-33Cb0e;Tb 43 L1970F (5908C>T) (11) G863A (2588G>C) (17) 44 6006-16Ab0e;G (16) 18 2654-36Cb0e;T (4) I2023I (6069Cb0e;T) (14) T897I (2690C>T) (7) L2027F (6079C>T) (14) 19 R943Q (2828Gb0e;A) (13) 45 V2050L (6148G>C) (14) Y954D (2860T>G) (4) 46 R2107H (6320G>A) (18) N965S (2894A>G) (14) 6386 d19; 2G>C (10) 20 G978D (2933G>A) (4) 47 R2139W (6415C>T) (14) L988L (2964Cb0e;T) (4) R2149L (6446G>T) (4) 21 E1022K (3064G>A) (4) C2150Y (6449G>A) (19) A1038V (3113C>T) (14) 48 D2177N (6529G>A) (17) G1050D (3149G>A) (4) L2241V (6721C>G) (12) 3211_3212insGT (14) 6729 af9; 21Cb0e;T (15) 22 E1087K (3259G>A) (14) 49 6730-3Tb0e;C (15) R1098C (3292C>T) (12) S2255I (6764Gb0e;T) (13) S1099P (3295T>C) (4) 6816 af9; 28Gb0e;C (4) R1108C (3322C>T) (14) R1129L (3386G>T) (17) a Bold indicates disease-causing mutations. Login to comment

[hide] Three families displaying the combination of Starg... Ophthalmology. 2004 Mar;111(3):546-53. Klevering BJ, Maugeri A, Wagner A, Go SL, Vink C, Cremers FP, Hoyng CB
Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.
Ophthalmology. 2004 Mar;111(3):546-53., [PMID:15019334]

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

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31 546 (c) 2004 by the American Academy of Ophthalmology ISSN 0161-6420/04/$-see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2003.06.010 study (D2177N and G1961E) were evaluated in a larger investigation including 1218 unrelated AMD patients and 1258 comparison individuals. Login to comment
32 The 2 sequence changes were found in 3.4% of the AMD patients and in approximately 0.95% of the control subjects, and it was concluded that the risk of AMD is elevated approximately 3-fold in D2177N carriers and approximately 5-fold in G1961E carriers.14 Other groups, however, could not find a significant difference in the prevalence of heterozygous ABCA4 mutations in exudative and dry AMD patients and control groups, although the numbers of individuals analyzed in these studies were smaller.15-20 In the proposed genotype-phenotype model for ABCA4 there is an inverse relationship between the presumed residual ABCA4 function and the severity of the retinal dystrophy.2,6,21 Because different combinations of ABCA4 mutations lead to different phenotypes, this model implicitly predicts the occurrence of families harboring different types of ABCA4-associated retinal disorders.2,3,6,7 In this study, we present the clinical and genetic findings in 3 families with multiple ABCA4-associated retinal disorders. Login to comment

[hide] Functional analysis of genetic mutations in nucleo... Biochemistry. 2003 Sep 16;42(36):10683-96. Biswas-Fiss EE
Functional analysis of genetic mutations in nucleotide binding domain 2 of the human retina specific ABC transporter.
Biochemistry. 2003 Sep 16;42(36):10683-96., [PMID:12962493]

Abstract [show]
The rod outer segment (ROS) ABC transporter (ABCR) plays an important role in the outer segment of retinal rod cells, where it functions as a transporter of all-trans retinal, most probably as the complex lipid, retinylidene-phosphatidyl-ethanolamine. We report here a quantitative analysis of the structural and functional effects of genetic mutations, associated with several macular degenerations, in the second nucleotide-binding domain of ABCR (NBD2). We have analyzed the ATP binding, kinetics of ATP hydrolysis, and structural changes. The results of these multifaceted analyses were correlated with the disease severity and prognosis. Results presented here demonstrated that, in wild type NBD2, distinct conformational changes accompany nucleotide (ATP and ADP) binding. Upon ATP binding, NBD2 protein changed to a relaxed conformation where tryptophans became more solvent-exposed, while ADP binding reverses this process and leads back to a taut conformation that is also observed with the unbound protein. This sequence of conformational change appears to be important in the energetics of the ATP hydrolysis and may have important structural consequences in the ability of the NBD2 domain to act as a regulator of the nucleotide-binding domain 1. Some of the mutant proteins displayed strikingly different patterns of conformational changes upon nucleotide binding that pointed to unique structural consequences of these genetic mutations. The ABCR dysfunctions, associated with various retinopathies, are multifaceted in nature and include alterations in protein structure as well as the attenuation of ATPase activity and nucleotide binding.

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73 The NBD2 expression vector pET29aNBD2 was used as template, 12 cycles of PCR, and each cycle was 30 s at 95 °C, 30 s at 50 °C, and 15 min at 68°C using complimentary oligonucleotides to produce the mutations L1971R, R2038W, G2146D, K2175A, and D2177N. Login to comment
74 The primers used for mutagenesis were as follows: L1971R, CGC CCT GGA GAG TGC TTT GGC CTC CGG GGA GTG AAT GGT GCC GGC AAA AC; R2038W, CTT TAC CTT TAT GCC AGG CTT CGA GGT GTA CCA GC, G2146D, CTG GCC ATC ATG GTA AAG GAC GCC TTT CGA TGT AT; D2177N, ATC AAA TCC CCG AAG GAC AAC CTG CTT CCT GAC CTG AAC; K2175A, CA ATG AAG ATC AAA TCC CCG GCG GAC GAC CTG CTT CCT GA. All of the mutations were disease-associated with the exception of K2175A. Login to comment
103 The locations of the disease associated mutations investigated in this study; L1971R, R2038W, G2146D, L2027F, and D2177N are indicated. Login to comment
144 Here, we have used site-specific mutagenesis to create disease-related genetic mutations: L1971R, D2177N, L2027F, R2038W, and G2146D as well as a synthetic mutation, K2175A. Login to comment
153 Lane 1: protein molecular weight standards; lane 2, wild-type NBD2; lane 3, L2027F mutant; lane 4, L1971R mutant; lane 5, D2177N; lane 6, G2146D; lane 7, R2038W mutant; lane 8, K2175A. Login to comment
180 Unlike most NBD2 mutants, mutant NBD2 D2177N protein appears to have a higher specific activity and rate relative to the wild type (Figure 5). Login to comment
181 The D2177N mutation leads to hyperactivity of the enzyme as opposed to hypo- and null ABCR mutant phenotypes more frequently observed with NBD2 mutations (18). Login to comment
186 The substitution of a polar group for an acidic group in the mutation D2177N led to a small increase in the rate of hydrolysis (130 nmol/ min/mg) (Table 1). Login to comment
218 The ATP binding constants for D2177N and K2175A were determined similarly (Figures 6B,E). Login to comment
220 The Kd for D2177N was 2.3 × 10-6 M, while that of K2175A was 1.1 × 10-6 M. These Kd values represented 4- and 2-fold decrease, from that observed in the wild type, in the binding affinity for D2177N and K2175A, respectively. Login to comment
253 The curves represent a least squares nonlinear regression curve fit of the data representing the (A) L1971R mutant, (B) D2177N mutant, (C) G2146D mutant, (D) R2038W mutant, and (E) K2175A mutant. Login to comment
267 Stern Volmer plots of the (A) wild-type NBD2, (B) L1971R mutant, (C) L2027F mutant, (D) D2177N mutant, (E) R2038W mutant, (F) G2146D mutant, and (F) K2175A mutant. Login to comment
273 The D2177N mutant was described earlier to have elevated levels of ATPase activity. Login to comment
281 The data were consistent with the rate of ATP hydrolysis of D2177N being increased relative to that of the wild-type protein. Login to comment
291 The K2175A mutant was created to explore the charge interaction between this amino acid and neighboring amino acid D2177N. Login to comment
304 Mutation D2177N has been reported in individuals suffering AMD, which is late in onset and affects the elderly. Login to comment
307 Mutation D2177N led to a small increase in the rate of ATP hydrolysis accompanied by a small decrease in ATP binding affinity, as compared to the wild-type control. Login to comment
334 In the mutant, D2177N, the tryptophan residues in the NBD2‚ADP bound form were less accessible to the quencher, and only 16% quenching was observed as compared to 22% observed for wild-type NBD2‚ADP (Figure 7D, Table 1). Login to comment
336 In this mutant, the extent of quenching observed for NBD2-free was 27%, and was between that observed for NBD2‚ATP (37%) and NBD2‚ ADP (16%); hence, the general conformational pattern in D2177N was NBD2‚ATP(open) f NBD2(intermediate) f NBD2‚ ADP(taut). Login to comment
337 These data indicated that the relative magnitude of change, in going from open to taut was greater for the D2177N mutant; following ATP hydrolysis, the D2177N mutant protein assumed a more closed conformation than the wild-type protein. Login to comment
338 The D2177N mutant had an increased rate of hydrolysis that may be related to a transition to a more taut conformation upon hydrolysis of ATP to ADP. Login to comment

[hide] Detailed analysis of allelic variation in the ABCA... Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2868-75. Schmidt S, Postel EA, Agarwal A, Allen IC Jr, Walters SN, De la Paz MA, Scott WK, Haines JL, Pericak-Vance MA, Gilbert JR
Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.
Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2868-75., [PMID:12824224]

Abstract [show]
PURPOSE: Age-related maculopathy (ARM) is one of the most common causes of blindness in older adults worldwide. Sequence variants in a gene coding for a retina-specific ATP-binding cassette (ABCA4) transporter protein, which is responsible for a phenotypically similar Mendelian form of retinal disease, were proposed to increase the risk of ARM. To examine the potential relationship of ABCA4 sequence variation and ARM risk in an independent data set, a clinically well-characterized population of 165 multiplex patients with ARM from 70 families, 33 unaffected relatives, and 59 unrelated control subjects with confirmed absence of ARM was screened for variants in any of the 50 exons and exon-intron boundaries of this gene. METHODS: A combination of denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequencing was used to detect ABCA4 sequence variants. The data set was analyzed with both case-control and family-based association analysis methods. RESULTS: No evidence was found of significantly different allele frequencies of ABCA4 sequence variants in patients compared with control subjects, and no evidence for association or cosegregation with disease in family-based analyses. CONCLUSIONS: This study confirmed the very high degree of ABCA4 sequence polymorphism in the general population, which makes the detection of potential disease-associated alleles particularly challenging. While this study does not definitively exclude ABCA4 from contributing to a small or moderate fraction of ARM, it adds to the body of evidence suggesting that ABCA4 is not a major susceptibility gene for this disorder.

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100 We did not detect the variants G1961E (5882G3A, exon 42) and D2177N (6529G3A, exon 48) reported as disease-associated16 in any of the 257 samples screened in this study. Login to comment
102 In agreement with the DHPLC results, we did not detect G1961E and D2177N in this patient population. Login to comment
103 In our earlier work,18 we had detected the D2177N variant in two of our sporadic patients with ARM. Login to comment
158 However, the fact that we did not detect a single copy of the only variants that have so far been reported as potentially disease associated, G1961E (5882G3A) and D2177N (6529G3A), in any of our 165 patients with ARM, suggests that their contribution to this phenotype is small at best. Login to comment
170 The frequency of potentially disease-associated variants has been consistently estimated to be no higher than 1% in a nonpatient population.11,12,16,20 Because of uncertainty about the true effect size, we have assumed three plausible relative risk values for an ABCA4 variant: 5, estimated for G1961E;16 3, estimated for D2177N;16 and 1.5, the lower confidence limit for G1961E.16 Power calculations using commercial software (nQuery-Advisor; Statistical Solutions, Saugus, MA) and DSTPLAN (http://odin. Login to comment
183 However, it is not clear that the two sequence variants proposed to be disease-associated in humans (G1961E, D2177N) are equivalent to a null mutation, even though they were shown to have some effect on the function of the ABCA4 protein.46 An animal model can be an invaluable tool for assessing the potential significance of sequence variation in a candidate gene; however, caution is necessary in inferring functional consequences in the context of complex human disease from data generated on mice. Login to comment

[hide] ABCA4 sequence variants in Chinese patients with a... Ophthalmologica. 2003 Mar-Apr;217(2):111-4. Baum L, Chan WM, Li WY, Lam DS, Wang PB, Pang CP
ABCA4 sequence variants in Chinese patients with age-related macular degeneration or Stargardt's disease.
Ophthalmologica. 2003 Mar-Apr;217(2):111-4., [PMID:12592048]

Abstract [show]
ABCA4 gene sequence alterations cause Stargardt's disease (STGD) and may cause some age-related macular degeneration (AMD). We sought to shed light on these associations among Hong Kong Chinese by genotyping 140 AMD, 18 STGD and 95 normal control subjects for 15 ABCA4 exons which were reported to often contain AMD- or STGD-associated mutations. Sequence alterations R212H, T1428M, V1433I, T1572M, I2166M, IVS6-5T>G and IVS33+1G>T were found in AMD patients. T1428M and R2040X occurred in STGD patients. Control subjects displayed all the above missense alterations but no splicing or nonsense changes. Therefore, ABCA4 splicing mutations may be associated with a small proportion of AMD cases.

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16 However, one very large study revealed a significant association of D2177N and G1961E with AMD [20]. Login to comment
45 D2177N and G1961E have been associated with AMD, but we found these mutations in neither AMD, STGD nor control subjects [20]. Login to comment

[hide] Differential occurrence of mutations causative of ... Hum Mutat. 2002 Mar;19(3):189-208. Pang CP, Lam DS
Differential occurrence of mutations causative of eye diseases in the Chinese population.
Hum Mutat. 2002 Mar;19(3):189-208., [PMID:11857735]

Abstract [show]
Ethnic differences and geographic variations affect the frequencies and nature of human mutations. In the literature, descriptions of causative mutations of eye diseases in the Chinese population are few. In this paper we attempt to reveal molecular information on genetic eye diseases involving Chinese patients from published and unpublished works by us and other groups. Our studies on candidate genes of eye diseases in the Chinese population in Hong Kong include MYOC and TISR for primary open angle glaucoma, RHO and RP1 for retinitis pigmentosa, ABCA4 and APOE for age-related macular degeneration, RB1 for retinoblastoma, APC for familial adenomatous polyposis with congenital hypertrophy of retinal pigment epithelium, BIGH3/TGFBI for corneal dystrophies, PAX6 for aniridia and Reiger syndrome, CRYAA and CRYBB2 for cataracts, and mtDNA for Leber hereditary optic neuropathy. We have revealed novel mutations in most of these genes, and in RHO, RP1, RB1, BIGH3, and PAX6 we have reported mutations that contribute to better understanding of the functions and properties of the respective gene products. We showed absence of MYOC does not necessarily cause glaucoma. No disease causative mutations have been identified in MYOC or ABCA4. There are similarities in the patterns of sequence alterations and phenotype-genotype associations in comparison with other ethnic groups, while the MYOC, RB1, APC, and PAX6 genes have more Chinese-specific sequence alterations. Establishment of a mutation database specific for the Chinese is essential for identification of genetic markers with diagnostic, prognostic, or pharmacological values.

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168 Several studies found no significant association [Stone et al., 1998; Rivera et al., 2000; Webster et al., 2001], but the largest study to date showed a significant association of two mutations with AMD: D2177N in 1.8% of AMD cases and 0.6% of controls (p = 0.005), and G1961E in 1.6% of AMD and 0.3% of controls (p = 0.0008) [Allikmets, 2000]. Login to comment

[hide] Genotype-phenotype analysis of ABCR variants in ma... Invest Ophthalmol Vis Sci. 2002 Feb;43(2):466-73. Bernstein PS, Leppert M, Singh N, Dean M, Lewis RA, Lupski JR, Allikmets R, Seddon JM
Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings.
Invest Ophthalmol Vis Sci. 2002 Feb;43(2):466-73., [PMID:11818392]

Abstract [show]
PURPOSE: Single-copy variants of the autosomal recessive Stargardt disease (STGD1) gene ABCR (ABCA4) have been shown to confer enhanced susceptibility to age-related macular degeneration (AMD). To investigate the role of ABCR alleles in AMD further, genotype-phenotype analysis was performed on siblings of patients with AMD who had known ABCR variants. This genetically related population provides a cohort of subjects with similar age and ethnic background for genotype-phenotype comparison to the original probands. METHODS: All available siblings of 26 probands carrying probable disease-associated ABCR variants were examined clinically. Blood samples were collected from these siblings for genotype analysis to search for the ABCR variant alleles corresponding to the isofamilial proband. RESULTS: Nineteen of 33 siblings from 15 families carried the respective proband's variant ABCR allele. Some families exhibited concordance of ABCR alleles with macular degeneration phenotype, but others did not. Exudative AMD was uncommon among both probands and siblings. CONCLUSIONS: Although population studies have indicated that some ABCR variant alleles may enhance susceptibility to AMD, investigation of the extent of ABCR involvement by kindred analysis is complicated by a plethora of environmental and other hereditary factors not investigated in the current study that may also play important roles.

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14 We reported that 16% of an initial cadre of patients with AMD (26/167) had heterozygous ABCR variants that resulted in non-conservative amino acid substitutions, frameshifts, or splice-site changes that were found in less than 1% of a general population control cohort.14 Two variants, G1961E and D2177N, accounted for half of the reported disease-associated variants, whereas the others were rare variants found in one or two affected individuals.14 Two groups subsequently reported much lower rates of potential disease-associated ABCR variants in their cohorts of patients with AMD,15-17 but their selected populations, clinical criteria, and mutation detection rates differed substantially from the initial study.18 More recently, however, a large multicenter international consortium confirmed that G1961E and D2177N variants of ABCR are indeed found in patients with AMD at a significantly higher frequency relative to control subjects.19 The two variants were found in 3.4% of patients with AMD (40/1189) versus 0.95% of control subjects (12/ 1258; P Ͻ 0.0001).19 We postulate that relatives of patients with Stargardt disease and of patients with AMD who are heterozygous carriers of the same variant ABCR alleles as the family proband may have an increased risk of development of AMD under some circumstances. Login to comment
52 AMD Grade of Probands Carrying Heterozygous ABCR Variants ABCR Variant Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 E471K 0 0 1 1 0 P940R* 0 0 0 1 0 T1428M 0 0 1 0 0 R1517S 0 0 0 1 0 I1562T 0 0 1 1 0 G1578R 0 0 1 0 0 5196ϩ1G3A 0 0 1 0 0 R1898H 0 0 0 1 0 G1961E 0 0 2 4 0 L1970F 0 0 1 0 0 6519⌬11bp 0 0 0 1 0 D2177N 0 1 3 3 0 6568⌬C 0 0 0 0 1 Data are number of probands at each grade. Login to comment
66 Statistical analysis becomes even more challenging if individual ABCR variants are examined, because the number of subjects becomes quite small, but two variants, G1961E and D2177N, deserve special attention. Login to comment
68 Four of seven siblings of D2177N probands who also carried the variant allele had grade 2 or greater maculopathy, whereas four of five siblings who did not carry the variant D2177N allele had grade 2 or greater maculopathy. Login to comment
74 segregation of the family`s D2177N ABCR allele with AMD phenotype (Fig. 4). Login to comment
75 The eldest sibling had moderate (grade 3) AMD, but did not carry the family proband`s D2177N ABCR variant. Login to comment
76 Two siblings (one older and one younger than the proband) carried the D2177N variant and exhibited mild to moderate AMD, whereas two others (one older and one younger than the proband) carried the variant but exhibited no signs of AMD. Login to comment
115 Our study of the D2177N and G1961E mutations in age-matched ophthalmoscopically examined control subjects confirms that an ABCR variant does not by itself confer an AMD phenotype in all cases, but may increase susceptibility to the complex trait when large populations are examined.19 The fact that many siblings have AMD without the same ABCR variant as the family proband is not unexpected, especially because there are likely to be other inherited and environmental risk factors that have not yet been identified that may act alone or in concert with ABCR alleles to enhance susceptibility to AMD. Login to comment
129 This is a recurring problem facing investigators studying other complex adult-onset multifactorial diseases, such as breast cancer and prostate cancer.46,47 Statistical power analysis indicates that we would need 144 siblings to achieve an 80% power of detecting a statistically significant elevated risk at P ϭ 0.05 if the study population prevalence of AMD is assumed to be 10% and the elevated risk of AMD conferred by any AMD-associated ABCR variant is comparable to the approximately threefold elevation in AMD risk found for the G1961E and D2177N ABCR variants in the International ABCR Consortium Study.19 Although there is mounting evidence that heterozygous variants in ABCR contribute to AMD susceptibility, we should not expect consistent concordance of variant alleles with AMD phenotype, because it is a complex trait influenced by a multitude of other hereditary and environmental risk factors. Login to comment

[hide] Cosegregation and functional analysis of mutant AB... Hum Mol Genet. 2001 Nov 1;10(23):2671-8. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.
Hum Mol Genet. 2001 Nov 1;10(23):2671-8., [PMID:11726554]

Abstract [show]
Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal recessively inherited retinopathies, including Stargardt disease (STGD), cone-rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD 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 AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.

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22 A subsequent multicenter international study confirmed this initial association for two specific disease-associated variants (G1961E and D2177N) and estimated a 3-5-fold increased risk for development of AMD among carriers of these two ABCR mutations (20). Login to comment
114 Sun et al. (28) reported substantial defects in protein expression or ATP binding of eight AMD-associated mutations (R212C, G863A, A1038V, R1108C, R1129L, P1380L, G1961E and L2027F) and an abnormal increase in the ATPase activity of the D2177N mutation, and they reported mild defects or wild-type activity within the sensitivity of the assay in four other AMD-associated variants (E471K, C1488R, T1526M and R1898H). Login to comment

[hide] Mutational scanning of the ABCR gene with double-g... Hum Genet. 2001 Sep;109(3):326-38. Fumagalli A, Ferrari M, Soriani N, Gessi A, Foglieni B, Martina E, Manitto MP, 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. 2001 Sep;109(3):326-38., [PMID:11702214]

Abstract [show]
Mutations in the retina-specific ABC transporter (ABCR) gene are responsible for autosomal recessive Stargardt disease (arSTGD). Mutation detection efficiency in ABCR in arSTGD patients ranges between 30% and 66% in previously published studies, because of high allelic heterogeneity and technical limitations of the employed methods. Conditions were developed to screen the ABCR gene by double-gradient denaturing-gradient gel electrophoresis. The efficacy of this method was evaluated by analysis of DNA samples with previously characterized ABCR mutations. This approach was applied to mutation detection in 44 Italian arSTGD patients corresponding to 36 independent genomes, in order to assess the nature and frequency of the ABCR mutations in this ethnic group. In 34 of 36 (94.4%) STGD patients, 37 sequence changes were identified, including 26 missense, six frameshift, three splicing, and two nonsense variations. Among these, 20 had not been previously described. Several polymorphisms were detected in affected individuals and in matched controls. Our findings extend the spectrum of mutations identified in STGD patients and suggest the existence of a subset of molecular defects specific to the Italian population. The identification of at least two disease-associated mutations in four healthy control individuals indicates a higher than expected carrier frequency of variant ABCR alleles in the general population. Genotype-phenotype analysis in our series showed a possible correlation between the nature and location of some mutations and specific ophthalmoscopic features of STGD disease.

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37 DNA samples (n=22) carrying previously identified mutations in the ABCR gene were employed as controls for evaluating the efficacy of the DG-DGGE approach in detecting sequence variations R572Q (Lewis et al. 1999), Y639X (Lewis et al. 1999), G863A (Lewis et al. 1999; Maugeri et al. 1999), A1038V (Rozet et al. 1998), T1019M (Rozet et al. 1998), 3211insGT (Lewis et al. 1999), P1380L (Lewis et al. 1999), H1406Y (Lewis et al. 1999), 4947delC (Lewis et al. 1999), H1838Y (Lewis et al. 1999), 5714+5G→A (Cremers et al. 1998), N1868I (De La Paz et al. 1999), L1938L (Rivera et al. 2000), G1961E (Allikmets et al. 1997a, 1997b), L1970F (Lewis et al. 1999), L2027F (Nasonkin et al. 1998), V2050L (Lewis et al. 1999), E2131K (Lewis et al. 1999), R2139W (Lewis et al. 1999), 6709insG (Lewis et al. 1999), D2177N (Allikmets et al. 1997a, 1997b), 2181del12 (Lewis et al. 1999). Login to comment

[hide] Variation of codons 1961 and 2177 of the Stargardt... Arch Ophthalmol. 2001 May;119(5):745-51. Guymer RH, Heon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, McNeil RJ, Haines H, Sheffield VC, Stone EM
Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration.
Arch Ophthalmol. 2001 May;119(5):745-51., [PMID:11346402]

Abstract [show]
OBJECTIVES: To investigate the role of 2 specific alleles of the Stargardt disease gene (ABCA4) in the pathogenesis of age-related macular degeneration (AMD). Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD. METHODS: Five hundred forty-four patients with AMD and 689 controls were ascertained from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion and single-strand conformation polymorphism analysis of polymerase chain reaction amplification products. Detected alleles were confirmed by DNA sequencing. The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups using a 2-tailed Fisher exact test. RESULTS: There was no significant difference (P >.1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast, there was a significant difference (P< .001) in the frequency of the G1961E alleles between normal individuals of Somali ancestry (11.3%) and normal individuals from other populations (0.4%). There was no evidence of cosegregation of these alleles and the AMD phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%). CONCLUSIONS: Somali ancestry is more than 100 times more strongly associated with presence of the G1961E allele than the AMD phenotype. This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD. CLINICAL RELEVANCE: The ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration. However, it does not seem to be involved in a statistically significant fraction of AMD cases.

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1 Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD. Login to comment
7 Results: There was no significant difference (PϾ.1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). Login to comment
12 This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD. Login to comment
24 (1) The primary purpose was to try to clarify the role of ABCA4 in AMD by screening a large cohort of patients with AMD and ethnically matched controls for the presence of the 2 sequence variations (G1961E and D2177N) that were most highly associated with AMD in the study by Allikmets et al.7 (2) A secondary purpose was to investigate the variation in allele frequency of G1961E among selected ethnic groups. Login to comment
25 (3) The final purpose was to examine the segregation of the G1961E and D2177N alleles in 5 multiplex families with AMD from Australia. Login to comment
26 RESULTS The distributions of G1961E and D2177N sequence variations in the various AMD and control populations are summarized in Table 1. Login to comment
28 Five instances of the G1961E variation and 7 instances of the D2177N change were observed among the patients with AMD, while 3 instances of G1961E and 4 of D2177N were observed among the controls. Login to comment
30 A Fisher exact test revealed the differences in allele frequency between these groups to be insignificant whether the alleles were considered together or separately (PϾ.10 in all cases) even without correction for multiple measurements.27 Collectively, the G1961E and D2177N sequence changes were found in 2.2% of the 544 patients with AMD in this study, ranging from 0.99% in patients from the United States to 5.1% in patients from Switzerland. Login to comment
45 The D2177N allele was detected by single-strand conformation polymorphism analysis. Login to comment
49 STATISTICAL ANALYSIS The proportion of subjects showing the G1961E or D2177N variant were compared between AMD and control groups using the Fisher exact test (2-tailed). Login to comment
61 Five of the 7 AMD probands from Australia who harbored a G1961E or D2177N change had family members who also carried the clinical diagnosis of AMD. Login to comment
64 Of the 15 family members diagnosed with AMD, 8 harbored a G1961E or D2177N change. Login to comment
68 The G1961E or D2177N sequence variations were found in 6 of the patients (2.7%) with CNV and 6 of the patients (2.5%) who were free from this complication. Login to comment
133 Therefore, in this study, we focused on the 2 sequence variations (G1961E and D2177N) that were most plausibly associated with AMD in the study by Allikmets et al.7 In that study, Allikmets and colleagues found evidence that one or the other of those 2 sequence variations were found in approximately 8% of patients with AMD (one-half of the total ABCA4 association they observed). Login to comment
134 Although these 2 sequence variations were statistically associated with AMD when considered by themselves,7 there was no statistical association with AMD if all of the observed missense variations were included in the analysis, or alternatively, if all of the various subgroup analyses were subjected to a statistical correction for multiple measurements.16 In this study, we failed to find any statistically significant association between AMD and the presence of the G1961E and D2177N ABCA4 sequence variations. Login to comment
146 A plus indicates the presence of a heterozygous ABCA4 sequence variation that was present in the family`s proband (G1961E for family 1, and D2177N for families 2-5). Login to comment
150 The sample size of this study was also large enough to result in a 95% power (␣=.05) to detect such a 3-fold difference if the frequency in the AMD cohort was as large as had been previously suggested (ie, 7.8% vs 2.6%).7 An interesting observation in the study by Allikmets and coauthors7 was that the G1961E and D2177N sequence variations were more commonly found in patients who had not experienced CNV. Login to comment
153 Of the 12 patients with AMD in this study who harbor G1961E or D2177N sequence variations, 6 had CNV. Login to comment
164 Her visual acuity in this eye was hand motions. She was found to harbor the D2177N allele. Login to comment
166 Her visual acuity in this eye was hand motions. She was found to harbor the D2177N allele. Login to comment
168 His visual acuity was 20/100 OS. Although 2 of his 3 relatives harbored the D2177N allele, he did not. Login to comment
170 Her visual acuity was 20/100 OD. Although 2 of her 3 relatives harbored the D2177N allele, she did not. Login to comment
174 In the present study, we examined all of the siblings of 5 families affected with AMD who were also found to harbor a G1961E or D2177N ABCA4 allele. Login to comment
27 RESULTS The distributions of G1961E and D2177N sequence variations in the various AMD and control populations are summarized in Table 1. Login to comment
29 Five instances of the G1961E variation and 7 instances of the D2177N change were observed among the patients with AMD, while 3 instances of G1961E and 4 of D2177N were observed among the controls. Login to comment
31 A Fisher exact test revealed the differences in allele frequency between these groups to be insignificant whether the alleles were considered together or separately (P..10 in all cases) even without correction for multiple measurements.27 Collectively, the G1961E and D2177N sequence changes were found in 2.2% of the 544 patients with AMD in this study, ranging from 0.99% in patients from the United States to 5.1% in patients from Switzerland. Login to comment
46 The D2177N allele was detected by single-strand conformation polymorphism analysis. Login to comment
50 STATISTICAL ANALYSIS The proportion of subjects showing the G1961E or D2177N variant were compared between AMD and control groups using the Fisher exact test (2-tailed). Login to comment
62 Five of the 7 AMD probands from Australia who harbored a G1961E or D2177N change had family members who also carried the clinical diagnosis of AMD. Login to comment
65 Of the 15 family members diagnosed with AMD, 8 harbored a G1961E or D2177N change. Login to comment
69 The G1961E or D2177N sequence variations were found in 6 of the patients (2.7%) with CNV and 6 of the patients (2.5%) who were free from this complication. Login to comment
135 Although these 2 sequence variations were statistically associated with AMD when considered by themselves,7 there was no statistical association with AMD if all of the observed missense variations were included in the analysis, or alternatively, if all of the various subgroup analyses were subjected to a statistical correction for multiple measurements.16 In this study, we failed to find any statistically significant association between AMD and the presence of the G1961E and D2177N ABCA4 sequence variations. Login to comment
147 A plus indicates the presence of a heterozygous ABCA4 sequence variation that was present in the family`s proband (G1961E for family 1, and D2177N for families 2-5). Login to comment
151 The sample size of this study was also large enough to result in a 95% power (a=.05) to detect such a 3-fold difference if the frequency in the AMD cohort was as large as had been previously suggested (ie, 7.8% vs 2.6%).7 An interesting observation in the study by Allikmets and coauthors7 was that the G1961E and D2177N sequence variations were more commonly found in patients who had not experienced CNV. Login to comment
154 Of the 12 patients with AMD in this study who harbor G1961E or D2177N sequence variations, 6 had CNV. Login to comment
165 Her visual acuity in this eye was hand motions. She was found to harbor the D2177N allele. Login to comment
167 Her visual acuity in this eye was hand motions. She was found to harbor the D2177N allele. Login to comment
169 His visual acuity was 20/100 OS. Although 2 of his 3 relatives harbored the D2177N allele, he did not. Login to comment
171 Her visual acuity was 20/100 OD. Although 2 of her 3 relatives harbored the D2177N allele, she did not. Login to comment
175 In the present study, we examined all of the siblings of 5 families affected with AMD who were also found to harbor a G1961E or D2177N ABCA4 allele. Login to comment

[hide] An analysis of allelic variation in the ABCA4 gene... Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM
An analysis of allelic variation in the ABCA4 gene.
Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89., [PMID:11328725]

Abstract [show]
PURPOSE: To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS: A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS: There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS: Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

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102 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 2 106delT FS NS 0 0 1 Ͻ0.01 2 160 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 3 161G 3 A Cys54Tyr NS 0 0 6 Ͻ0.01 3 179C 3 T Ala60Val NS 0 0 2 Ͻ0.01 3 194G 3 A Gly65Glu NS 0 0 2 Ͻ0.01 3 223T 3 G Cys75Gly NS 0 0 2 Ͻ0.01 3 247delCAAA FS NS 0 0 2 Ͻ0.01 3 298C 3 T Ser100Pro NS 0 0 1 Ͻ0.01 5 454C 3 T Arg152Stop NS 0 0 2 Ͻ0.01 6 574G 3 A Ala192Thr NS 0 0 1 Ͻ0.01 6 618C 3 G Ser206Arg NS 0 0 3 Ͻ0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 Ͻ0.01 6 661delG FS NS 0 0 1 Ͻ0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 Ͻ0.01 6 746A 3 C Asp249Gly NS 0 0 1 Ͻ0.01 8 899C 3 A Thr300Asn NS 0 0 1 Ͻ0.01 8 997C 3 T Arg333Trp NS 0 0 1 Ͻ0.01 9 1140T 3 A Asn380Lys NS 0 0 1 Ͻ0.01 9 1222C 3 T Arg408Stop NS 0 0 1 Ͻ0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 Ͻ0.01 10 1344delG FS NS 0 0 1 Ͻ0.01 11 1411G 3 A Glu471Lys NS 0 0 3 Ͻ0.01 11 1513delATCAC FS NS 0 0 1 Ͻ0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 Ͻ0.01 13 1805G 3 A Arg602Gln NS 0 0 1 Ͻ0.01 13 1819G 3 T Gly607Trp NS 0 0 1 Ͻ0.01 13 1823T 3 A Phe608Ile NS 0 0 1 Ͻ0.01 13 1927G 3 A Val643Met NS 0 0 1 Ͻ0.01 14 1989G 3 T Trp663Stop NS 0 0 1 Ͻ0.01 14 2005delAT FS NS 0 0 3 Ͻ0.01 14 2041C 3 T Arg681Stop NS 0 0 2 Ͻ0.01 14 2147C 3 T Thr716Met NS 0 0 1 Ͻ0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 Ͻ0.01 15 2294G 3 A Ser765Asn NS 0 0 1 Ͻ0.01 15 2300T 3 A Val767Asp NS 0 0 2 Ͻ0.01 16 2385del16bp FS NS 0 0 1 Ͻ0.01 16 2453G 3 A Gly818Glu NS 0 0 1 Ͻ0.01 16 2461T 3 A Trp821Arg NS 0 0 1 Ͻ0.01 16 2546T 3 C Val849Ala NS 0 0 4 Ͻ0.01 16 2552G 3 A Gly851Asp NS 0 0 1 Ͻ0.01 16 2560G 3 A Ala854Thr NS 0 0 1 Ͻ0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 Ͻ0.01 18 2690C 3 T Thr897Ile NS 0 0 1 Ͻ0.01 18 2701A 3 G Thr901Ala NS 0 1 0 Ͻ0.01 18 2703A 3 G Thr901Arg NS 0 0 2 Ͻ0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 Ͻ0.01 20 2894A 3 G Asn965Ser NS 0 0 3 Ͻ0.01 19 2912C 3 A Thr971Asn NS 0 0 1 Ͻ0.01 19 2915C 3 A Thr972Asn NS 0 0 1 Ͻ0.01 20 2920T 3 C Ser974Pro NS 0 0 1 Ͻ0.01 20 2966T 3 C Val989Ala NS 0 0 2 Ͻ0.01 20 2977del8bp FS NS 0 0 1 Ͻ0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 Ͻ0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 Ͻ0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 Ͻ0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 Ͻ0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 Ͻ0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 Ͻ0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 Ͻ0.01 22 3323G 3 A Arg1108His NS 0 0 1 Ͻ0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 Ͻ0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 Ͻ0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 Ͻ0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 Ͻ0.01 26 3835delGATTCT FS NS 0 0 1 Ͻ0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 Ͻ0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 Ͻ0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 Ͻ0.01 28 4234C 3 T Gln1412stop NS 0 0 1 Ͻ0.01 29 4297G 3 A Val1433Ile NS 1 0 0 Ͻ0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 Ͻ0.01 30 4353 - 1g 3 t Splice site NS 0 0 1 Ͻ0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 Ͻ0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 Ͻ0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 Ͻ0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 Ͻ0.01 30 4531insC FS NS 0 0 2 Ͻ0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 Ͻ0.01 30 4539 ϩ 1g 3 t Splice site NS 0 0 1 Ͻ0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 Ͻ0.01 33 4733delGTTT FS NS 0 0 1 Ͻ0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 Ͻ0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 Ͻ0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 Ͻ0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 Ͻ0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 Ͻ0.01 36 5077G 3 A Val1693Ile NS 0 0 1 Ͻ0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 Ͻ0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 Ͻ0.01 36 5212del11bp FS NS 0 0 1 Ͻ0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 Ͻ0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 Ͻ0.01 37 5288delG FS NS 0 0 1 Ͻ0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 Ͻ0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 Ͻ0.01 39 5584 ϩ 5g 3 a Splice site 0.02 Yes 0 0 6 Ͻ0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 Ͻ0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 Ͻ0.01 40 5687T 3 A Val1896Asp NS 0 0 1 Ͻ0.01 40 5693G 3 A Arg1898His NS 0 0 1 Ͻ0.01 40 5714 ϩ 5g 3 a Splice site NS 0 0 1 Ͻ0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu Ͻ0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 Ͻ0.01 43 5917delG FS NS 0 0 1 Ͻ0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 Ͻ0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 Ͻ0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 Ͻ0.01 45 6148A 3 C Val2050Leu NS 1 0 0 Ͻ0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 Ͻ0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 Ͻ0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 Ͻ0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 Ͻ0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 Ͻ0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 Ͻ0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 Ͻ0.01 48 6707delTCACACAG FS NS 0 0 1 Ͻ0.01 48 6729 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 Ͻ0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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103 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 2 106delT FS NS 0 0 1 b0d;0.01 2 160 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 3 161G 3 A Cys54Tyr NS 0 0 6 b0d;0.01 3 179C 3 T Ala60Val NS 0 0 2 b0d;0.01 3 194G 3 A Gly65Glu NS 0 0 2 b0d;0.01 3 223T 3 G Cys75Gly NS 0 0 2 b0d;0.01 3 247delCAAA FS NS 0 0 2 b0d;0.01 3 298C 3 T Ser100Pro NS 0 0 1 b0d;0.01 5 454C 3 T Arg152Stop NS 0 0 2 b0d;0.01 6 574G 3 A Ala192Thr NS 0 0 1 b0d;0.01 6 618C 3 G Ser206Arg NS 0 0 3 b0d;0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 b0d;0.01 6 661delG FS NS 0 0 1 b0d;0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 b0d;0.01 6 746A 3 C Asp249Gly NS 0 0 1 b0d;0.01 8 899C 3 A Thr300Asn NS 0 0 1 b0d;0.01 8 997C 3 T Arg333Trp NS 0 0 1 b0d;0.01 9 1140T 3 A Asn380Lys NS 0 0 1 b0d;0.01 9 1222C 3 T Arg408Stop NS 0 0 1 b0d;0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 b0d;0.01 10 1344delG FS NS 0 0 1 b0d;0.01 11 1411G 3 A Glu471Lys NS 0 0 3 b0d;0.01 11 1513delATCAC FS NS 0 0 1 b0d;0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 b0d;0.01 13 1805G 3 A Arg602Gln NS 0 0 1 b0d;0.01 13 1819G 3 T Gly607Trp NS 0 0 1 b0d;0.01 13 1823T 3 A Phe608Ile NS 0 0 1 b0d;0.01 13 1927G 3 A Val643Met NS 0 0 1 b0d;0.01 14 1989G 3 T Trp663Stop NS 0 0 1 b0d;0.01 14 2005delAT FS NS 0 0 3 b0d;0.01 14 2041C 3 T Arg681Stop NS 0 0 2 b0d;0.01 14 2147C 3 T Thr716Met NS 0 0 1 b0d;0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 b0d;0.01 15 2294G 3 A Ser765Asn NS 0 0 1 b0d;0.01 15 2300T 3 A Val767Asp NS 0 0 2 b0d;0.01 16 2385del16bp FS NS 0 0 1 b0d;0.01 16 2453G 3 A Gly818Glu NS 0 0 1 b0d;0.01 16 2461T 3 A Trp821Arg NS 0 0 1 b0d;0.01 16 2546T 3 C Val849Ala NS 0 0 4 b0d;0.01 16 2552G 3 A Gly851Asp NS 0 0 1 b0d;0.01 16 2560G 3 A Ala854Thr NS 0 0 1 b0d;0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 b0d;0.01 18 2690C 3 T Thr897Ile NS 0 0 1 b0d;0.01 18 2701A 3 G Thr901Ala NS 0 1 0 b0d;0.01 18 2703A 3 G Thr901Arg NS 0 0 2 b0d;0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 b0d;0.01 20 2894A 3 G Asn965Ser NS 0 0 3 b0d;0.01 19 2912C 3 A Thr971Asn NS 0 0 1 b0d;0.01 19 2915C 3 A Thr972Asn NS 0 0 1 b0d;0.01 20 2920T 3 C Ser974Pro NS 0 0 1 b0d;0.01 20 2966T 3 C Val989Ala NS 0 0 2 b0d;0.01 20 2977del8bp FS NS 0 0 1 b0d;0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 b0d;0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 b0d;0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 b0d;0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 b0d;0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 b0d;0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 b0d;0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 b0d;0.01 22 3323G 3 A Arg1108His NS 0 0 1 b0d;0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 b0d;0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 b0d;0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 b0d;0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 b0d;0.01 26 3835delGATTCT FS NS 0 0 1 b0d;0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 b0d;0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 b0d;0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 b0d;0.01 28 4234C 3 T Gln1412stop NS 0 0 1 b0d;0.01 29 4297G 3 A Val1433Ile NS 1 0 0 b0d;0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 b0d;0.01 30 4353 afa; 1g 3 t Splice site NS 0 0 1 b0d;0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 b0d;0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 b0d;0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 b0d;0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 b0d;0.01 30 4531insC FS NS 0 0 2 b0d;0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 b0d;0.01 30 4539 af9; 1g 3 t Splice site NS 0 0 1 b0d;0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 b0d;0.01 33 4733delGTTT FS NS 0 0 1 b0d;0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 b0d;0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 b0d;0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 b0d;0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 b0d;0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 b0d;0.01 36 5077G 3 A Val1693Ile NS 0 0 1 b0d;0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 b0d;0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 b0d;0.01 36 5212del11bp FS NS 0 0 1 b0d;0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 b0d;0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 b0d;0.01 37 5288delG FS NS 0 0 1 b0d;0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 b0d;0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 b0d;0.01 39 5584 af9; 5g 3 a Splice site 0.02 Yes 0 0 6 b0d;0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 b0d;0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 b0d;0.01 40 5687T 3 A Val1896Asp NS 0 0 1 b0d;0.01 40 5693G 3 A Arg1898His NS 0 0 1 b0d;0.01 40 5714 af9; 5g 3 a Splice site NS 0 0 1 b0d;0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu b0d;0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 b0d;0.01 43 5917delG FS NS 0 0 1 b0d;0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 b0d;0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 b0d;0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 b0d;0.01 45 6148A 3 C Val2050Leu NS 1 0 0 b0d;0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 b0d;0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 b0d;0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 b0d;0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 b0d;0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 b0d;0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 b0d;0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 b0d;0.01 48 6707delTCACACAG FS NS 0 0 1 b0d;0.01 48 6729 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 b0d;0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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[hide] Simple and complex ABCR: genetic predisposition to... Am J Hum Genet. 2000 Oct;67(4):793-9. Epub 2000 Sep 1. Allikmets R
Simple and complex ABCR: genetic predisposition to retinal disease.
Am J Hum Genet. 2000 Oct;67(4):793-9. Epub 2000 Sep 1., [PMID:10970771]

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57 In 1997, a joint study by four laboratories suggested Table 1 Meta-analysis of Published Data on Two ABCR Alleles STUDY D2177N G1961Ea No. of Cases No of. Login to comment
69 In that study, the two most common AMD-associated variants, G1961E and D2177N, were genotyped in 1,218 unrelated patients with AMD and in 1,258 reportedly unaffected, matched controls. Login to comment
72 The risk of AMD was estimated to be increased approximately threefold in carriers of D2177N and approximately fivefold in carriers of G1961E. Login to comment
81 Note that the relative risk estimates calculated on the basis of the meta-analysis are also increased compared with those in the consortium study (Allikmets 2000) and are estimated at ~4 for the D2177N mutation and at ~7 for the G1961E variant. Login to comment
115 For example, they demonstrate that both ABCR variants analyzed in the consortium study, G1961E and D2177N, affect the protein function in vitro. Login to comment
117 The D2177N variant had no effect on 8-azido-ATP binding but exhibited a reproducible elevation in ATPase activity, relative to the wild type (Sun et al. 2000). Login to comment

[hide] A comprehensive survey of sequence variation in th... Am J Hum Genet. 2000 Oct;67(4):800-13. Epub 2000 Aug 24. Rivera A, White K, Stohr H, Steiner K, Hemmrich N, Grimm T, Jurklies B, Lorenz B, Scholl HP, Apfelstedt-Sylla E, Weber BH
A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.
Am J Hum Genet. 2000 Oct;67(4):800-13. Epub 2000 Aug 24., [PMID:10958763]

Abstract [show]
Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD 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, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of approximately 58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.

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82 Table 3 Rare Sequence Variants in the ABCA4 Gene EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (288) AMD (400) Control (440) 5: 455GrA R152Q 3 1 3 This study 8: IVS8ϩ38ArT Unknown 0 1 0 This study 12: 1654GrA V552I 0 0 2 This study IVS11-6CrG Unknown 0 4 2 This study 13: 1932CrT D644D 2 0 0 This study 17: IVS16-12CrG Unknown 0 0 8 This study 18: IVS17-56CrG Unknown 3 0 0 This study IVS17-36CrT Unknown 0 2 1 This study 22: 3261ArC E1087D 1 0 0 This study 3264CrT P1088P 0 0 1 This study IVS21-20CrT Unknown 1 0 0 This study 23: IVS23ϩ10TrG Unknown 1 0 0 This study IVS23ϩ17GrC Unknown 1 0 0 This study 24: IVS23-28TrC Unknown 2 4 1 This study 25: 3759GrA T1253T 1 0 0 This study 28: 4140GrA P1380P 2 0 0 This study IVS28ϩ43GrA Unknown 4 3 1 This study 29: IVS29ϩ13GrA Unknown 0 1 0 This study IVS29ϩ32ArG Unknown 1 0 0 This study 31: 4578GrA T1526T 0 1 0 This study 32: IVS32ϩ45TrC Unknown 1 0 0 This study 33: IVS32-57TrG Unknown 0 0 1 This study 4685TrC I1562T 0 0 6 Allikmets et al. (1997b) 36: IVS36ϩ20GrA Unknown 1 0 0 This study 39: 5487GrT L1829L 0 0 1 This study IVS38-10TrC Unknown 9 0 0 Maugeri et al. (1999) 41: 5761GrA V1921M 1 1 1 This study 43: 5908CrT L1970F 1 0 1 Allikmets et al. (1997b), Rozet et al. (1998), Lewis et al. (1999) IVS43ϩ7ArC Unknown 1 0 0 This study 44: 6027CrT I2023I 1 0 0 Allikmets et al. (1997a), Nasonkin et al. (1998) 45: 6176GrC G2059A 0 0 1 This study 46: IVS46ϩ27GrA Unknown 0 0 1 This study 47: IVS46-46TrA Unknown 1 0 0 This study 48: IVS48ϩ21CrT Unknown 18a 2a 0 Allikmets et al. (1997b), Nasonkin et al. (1998), Papaioannou et al. (2000) 6529GrA D2177N 2 3 4 Allikmets et al. (1997b) 6721CrG L2241V 1 0 0 This study a Occurs together with G1961E in 17/18 and 2/2 instances. Login to comment
143 Under our definitions, the conservative amino acid alteration D2177N, which has been described elsewhere as associated with AMD (Allikmets et al. 1997a; Allikmets and the International ABCR Screening Consortium 2000), was also classified as a rare sequence variant. Login to comment
182 This stands in contrast to a recentP p .72 study, involving 15 research groups from the United States and Europe, that specifically investigated the frequency of two common ABCA4 variants, G1961E and D2177N, in a large cohort (11,200 individuals each) of patients with AMD and of controls (Allikmets and The International ABCR Screening Consortium 2000). Login to comment

[hide] Mutations in the ABCA4 (ABCR) gene are the major c... Am J Hum Genet. 2000 Oct;67(4):960-6. Epub 2000 Aug 24. Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, Hoyng CB, Cremers FP
Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.
Am J Hum Genet. 2000 Oct;67(4):960-6. Epub 2000 Aug 24., [PMID:10958761]

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

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32 Although the significance of this finding is under debate (Stone et al. 1998), at least two ABCA4 mutations (G1961E and D2177N) have been shown, in a large multicenter study, to be statistically more frequent in patients Table 1 ABCA4 Mutations in Patients with CRD PATIENT INHERITANCE ABCA4 ALLELE 1 ABCA4 ALLELE 2 Nucleotide Changes Effects Nucleotide Changes Effects 9250a Isolated 1622TrC;3113CrT L541P;A1038Vb 194GrA G65Eb 9303 AR 1622TrC;3113CrT L541P;A1038Vb 9336 Isolated 6658CrT Q2220X 9369a AR 6601-6602delAG Frameshift 9370 Isolated 1622TrC;3113CrT L541P;A1038Vb 9371 Isolated 1622TrC;3113CrT L541P;A1038Vb 1622TrC;3113CrT L541P;A1038Vb 9378a Isolated 768GrT 5 Splice mutationb 9553 AR 2588GrC DG863/G863Ab IVS35del-2rϩ2del4 3 Splice mutation 9633 Isolated 1622TrC;3113CrT L541P;A1038Vb 4469GrA C1490Yb 9650 Isolated 3364GrA E1122Kb 9887 Isolated 4793CrA A1598D 6329GrA W2110X 11872 Isolated 634CrT R212Cb 13163a AR 1622TrC;3113CrT L541P;A1038Vb IVS36ϩ1GrA 5 Splice mutationb a Patient with atypical CRD. Login to comment

[hide] Further evidence for an association of ABCR allele... Am J Hum Genet. 2000 Aug;67(2):487-91. Epub 2000 Jul 3. Allikmets R
Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium.
Am J Hum Genet. 2000 Aug;67(2):487-91. Epub 2000 Jul 3., [PMID:10880298]

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Age-related macular degeneration (AMD) accounts for >50% of the registered visual disability among North American and Western European populations and has been associated both with environmental factors, such as smoking, and with genetic factors. Previously we have reported disease-associated variants in the ABCR (also called ABCA4) gene in a subset of patients affected with this complex disorder. We have now tested our original hypothesis, that ABCR is a dominant susceptibility locus for AMD, by screening 1,218 unrelated AMD patients of North American and Western European origin and 1,258 comparison individuals from 15 centers in North America and Europe for the two most frequent AMD-associated variants found in ABCR. These two sequence changes, G1961E and D2177N, were found in one allele of ABCR in 40 patients ( approximately 3.4%), and in 13 control subjects ( approximately 0.95%). Fisher's two-sided exact test confirmed that these two variants are associated with AMD at a statistically significant level (P<.0001). The risk of AMD is elevated approximately threefold in D2177N carriers and approximately fivefold in G1961E carriers. The identification of a gene that confers risk of AMD is an important step in unraveling this complex disorder.

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6 These two sequence changes, G1961E and D2177N, were found in one allele of ABCR in 40 patients (~3.4%), and in 13 control subjects (~0.95%). Login to comment
8 The risk of AMD is elevated approximately threefold in D2177N carriers and approximatelyP ! Login to comment
21 We present new data on 1,218 patients with AMD and 1,258 matched controls studied at 15 centers (7 in the United States and 8 in Europe) to test the associations with AMD of two of the more common AMD-associated ABCR variants, G1961E and D2177N. Login to comment
27 Table 1 Association of G1961E and D2177N Alleles with AMD CENTER POPULATION AMD SAMPLES CONTROLS G1961E D2177N Dry Wet Total GP AM Total AMD (D/W) Control (GP/AM) AMD (D/W) Control (GP/AM) Boston/Salt Lake City/Baltimore Eur. Am. Login to comment
37 Genotyping of the G1961E and D2177N variants was performed by a method of choice at each center. Login to comment
46 D2177N was present in 21/1,189 (1.77%) AMD cases, compared with 8/1,258 (0.64%) controls (P = ). Login to comment
48 There was no statistically significant evidence of heterogeneity of odds ratios among units, and the prevalence of D2177N was higher in AMD cases in 8 of the 10 units with at least one D2177N allele. Login to comment
49 The combination of either G1961E or D2177N was found in 40/1,189 (3.36%) patients with AMD, compared with 12/1,258 (0.95%) control subjects (P ! Login to comment
65 Together, the G1961E and D2177N variants were present in 23/533 patients with nonexudative disease and in 17/685 with exudative lesions. Login to comment
75 For population stratification to explain the above associations at any one study center, ethnic (sub)groups in that center should both associate strongly with AMD prevalence and segregate concordantly with the prevalences of both G1961E and D2177N. Login to comment
80 It also seems unlikely that similar ethnic correlations should occur with G1961E and D2177N, which we have yet to find together in the same subject. Login to comment
85 The mutant G1961E protein, produced after the transfection of human embryonic kidney (293) cells with cloned cDNA, exhibits several-fold lower binding of 8- azido-ATP and inhibition of ATPase activity by retinal, as compared with the wild-type ABCR protein. Login to comment
86 The D2177N variant had no effect on 8-azido-ATP binding but exhibited a reproducible elevation in ATPase activity relative to the wild type (H. Sun, P. M. Smallwood, and J. Nathans, personal communication). Login to comment
92 In summary, new data from 15 centers in the United States and Europe independently confirm the association of ABCR alleles G1961E and D2177N with AMD. Login to comment
79 It also seems unlikely that similar ethnic correlations should occur with G1961E and D2177N, which we have yet to find together in the same subject. Login to comment
91 In summary, new data from 15 centers in the United States and Europe independently confirm the association of ABCR alleles G1961E and D2177N with AMD. Login to comment

[hide] Molecular genetic analysis of ABCR gene in Japanes... Jpn J Ophthalmol. 2000 May-Jun;44(3):245-9. Fuse N, Suzuki T, Wada Y, Yoshida M, Shimura M, Abe T, Nakazawa M, Tamai M
Molecular genetic analysis of ABCR gene in Japanese dry form age-related macular degeneration.
Jpn J Ophthalmol. 2000 May-Jun;44(3):245-9., [PMID:10913642]

Abstract [show]
PURPOSE: To explore whether the mutation in the retina-specific ATP-binding cassette transporter (ABCR) gene, the Stargardt's disease gene, contributes to the prevalence of the dry form of age-related macular degeneration (dry AMD) in Japanese unrelated patients. METHODS: Twenty-five Japanese unrelated patients with dry AMD who were diagnosed by fluorescein angiography and indocyanine green angiography were chosen as the dry AMD group. None of these cases had apparent choroidal neovascularization. To detect the mutations in the ABCR gene, genomic DNA was extracted from leukocytes of peripheral blood, and 26 exons of the ABCR gene were amplified by polymerase chain reaction (PCR). All the PCR products were then directly sequenced. When a mutation was detected, the occurrence of a mutation was compared between these AMD patients and the control group. RESULTS: After direct sequencing, a point mutation in exon 29 was found in one of the 25 dry AMD patients. In addition, a polymorphism in exon 45 was found in two other patients, and three sequence variations in exon 23 were detected in all patients. The incidence in AMD patients in whom a mutation in exon 29 (4%) was detected was less than that in controls (5%). Screening of the intron-exon boundaries also led to the identification of intronic mutation in intron 33. CONCLUSION: In this study we found no relationship between allelic variation in the ABCR gene and the prevalence of dry AMD in Japanese unrelated patients.

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31 Mutations Found in ABCR* Gene in 26 Exons Examined in This Study Exon AMD† Stargardt`s Disease Exon AMD Stargardt`s Disease 11 E471K 29 T1428M 15 31 R1517S 16 G818E, G863A (D847H) 33 I1562T G1578R 17 34 N1614FS 18 35 19 V931M, 2884delC N965M, (R943Q) 36 5196ϩ1G→A 5041deL15 5196ϩ2T→C 20 40 R1898H R1898H 21 A1028V 42 G1961E G1961E 22 3211insGT, V1072A E1087K 43 L1970F 6006ϩ1G→T 23 R1129L 44 L2027F, R2038W (I2023I) 24 45 V2050L, R2077W (I2083I) 25 46 R2106C (V2094V) 27 48 6519⌬11bp D2177N 6568⌬C 6519⌬11bp 6709insG *ABCR: ATP-binding cassette transporter. Login to comment

[hide] Analysis of the Stargardt disease gene (ABCR) in a... Ophthalmology. 1999 Aug;106(8):1531-6. De La Paz MA, Guy VK, Abou-Donia S, Heinis R, Bracken B, Vance JM, Gilbert JR, Gass JD, Haines JL, Pericak-Vance MA
Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration.
Ophthalmology. 1999 Aug;106(8):1531-6., [PMID:10442900]

Abstract [show]
PURPOSE: Age-related macular degeneration (AMD) is a complex genetic disorder and the leading cause of severe vision loss in the elderly. The Stargardt disease gene (ABCR) has been proposed as a major genetic risk factor in AMD. The purpose of this study was to evaluate the authors' AMD population for the specific ABCR variants proposed previously as genetic risk factors for AMD. METHODS: The authors screened their AMD population (159 familial cases from 112 multiplex families and 53 sporadic cases) and 56 racially matched individuals with no known history of AMD from the same clinic population for evidence of the ABCR variants. Grading of disease severity was performed according to a standard protocol. Patients with extensive intermediate drusen or large soft drusen, drusenoid retinal pigment epithelial (RPE) detachments, geographic atrophy of the RPE, or evidence of exudative maculopathy were considered affected. Analysis for variants was performed by polymerase chain reaction amplification of individual exons of the ABCR gene with flanking primers and a combination of single-strand conformation polymorphism, heteroduplex analysis, and high-performance liquid chromatography. All abnormal conformers detected using these techniques were characterized by direct sequencing. RESULTS: The authors identified only two of the previously reported variants in their study population. Both variants occurred in sporadic cases, and none was found in familial cases or the randomly selected population. In addition, the authors identified several newly described polymorphisms and variants in both the AMD and control populations. CONCLUSIONS: Based on these initial findings, the authors suggest that ABCR is not a major genetic risk factor for AMD in their study population. Additional genetic studies are needed to more fully evaluate the role of ABCR in AMD.

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80 The only variant we found in our study population was D2177N, Asp2177 3 Asn2177 .31 We identified this change in two of our sporadic AMD patients (3.8%) and in none of the familial or population cases. Login to comment
107 Number of Age-related Macular Degeneration (AMD) Cases with Variants* Mutation Duke (n ‫؍‬ 169)† D2177N 2 (1.2%) E471K 0 R1129L 0 T1428M 0 R1517S 0 I1562T 0 G1578R 0 5169 ϩ 1G 3 A 0 R1898H 0 G1961E 0 L1970F 0 6519⌬11bp 0 6568⌬C 0 Total 2 (1.2%) * Variants considered to be associated with the genetic etiology of AMD by Allikmets et al.31 † Independent cases are determined by counting 1 familial AMD case from each of the 112 families and adding the 57 sporadic AMD cases, for a total of 169 cases. Login to comment
111 In the report by Allikmets et al, the D2177N variant was one of the most common variants identified (7 [4.2%] of 167 individual AMD cases) and accounted for 27% of the ABCR variants among their AMD study population. Login to comment
112 One D2177N variant was identified among the 220 controls that they studied. Login to comment
134 With the exception of the D2177N variant in two AMD sporadic individuals, our collective findings differ significantly from those of Allikmets et al.31 Our observed rate of ABCR variants (1.2%) is significantly lower than their 16% (P Ͻ 0.00001). Login to comment

[hide] The rod photoreceptor ATP-binding cassette transpo... Vision Res. 1999 Jul;39(15):2537-44. Shroyer NF, Lewis RA, Allikmets R, Singh N, Dean M, Leppert M, Lupski JR
The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial.
Vision Res. 1999 Jul;39(15):2537-44., [PMID:10396622]

Abstract [show]
The ABCR gene encodes a rod photoreceptor specific ATP-binding cassette transporter. Mutations in ABCR are associated with at least four inherited retinal dystrophies: Stargardt disease, Fundus Flavimaculatus, cone-rod dystrophy, and retinitis pigmentosa. A statistically significant increase in heterozygous ABCR alterations has been identified in patients with age-related macular degeneration (AMD). A pedigree is described which manifests both Stargardt disease and AMD in which an ABCR mutation cosegregates with both disease phenotypes. These data from this case report support the hypothesis that ABCR is a dominant susceptibility locus for AMD. Recent work regarding ABCR is reviewed and a model is presented in which decreased ABCR function correlates with severity of retinal disease.

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68 The two most common AMD-associated mutations have similar frequencies in the Utah and Boston cohorts: D2177N was identified in five patients from Utah and two patients from Boston; G1961E was identified in two patients from Utah and four patients from Boston. Login to comment

[hide] Mutation of the Stargardt disease gene (ABCR) in a... Science. 1997 Sep 19;277(5333):1805-7. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M
Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.
Science. 1997 Sep 19;277(5333):1805-7., [PMID:9295268]

Abstract [show]
Age-related macular degeneration (AMD) 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. Here, 167 unrelated AMD patients were screened for alterations in ABCR, a gene that encodes a retinal rod photoreceptor protein and is defective in Stargardt disease, a common hereditary form of macular dystrophy. Thirteen different AMD-associated alterations, both deletions and amino acid substitutions, were found in one allele of ABCR in 26 patients (16%). Identification of ABCR alterations will permit presymptomatic testing of high-risk individuals and may lead to earlier diagnosis of AMD and to new strategies for prevention and therapy.

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87 One alteration, Asp2177 3 Asn2177 (D2177N) (23), was present in 7 of the 167 AMD patients and in only 1 of 220 controls, which is a significant difference by Fisher`s exact test (P ϭ 0.023). Login to comment
99 Mutation AMD (n ϭ167) STGD (n ϭ 98) General population (n ϭ 220) E471K 2 (1.2%) NA 0 (0%) R1129L 1 (0.6%) 0 (0%)* 0 (0%) T1428M 1 (0.6%) 0 (0%) 0 (0%) R1517S 1 (0.6%) 0 (0%) 0 (0%) I1562T 2 (1.2%) 0 (0%) 0 (0%) G1578R 1 (0.6%) 0 (0%) 0 (0%) 5196ϩ1G 3 A 1 (0.6%) 0 (0%) 0 (0%) R1898H 1 (0.6%) 4 (4%) 0 (0%) G1961E 6 (3.6%) 8 (8%) 0 (0%) L1970F 1 (0.6%) 0 (0%) 0 (0%) 6519⌬11bp 1 (0.6%)† 1 (1%)† 0 (0%) D2177N 7 (4.2%) 0 (0%) 1 (0.45%) 6568⌬C 1 (0.6%) 0 (0%) 0 (0%) Totals 26 (16%) 13 (13%) 1 (0.45%) *A substitution to a different amino acid (R1129C) was detected in one STGD1 patient. Login to comment
84 One alteration, Asp2177 3 Asn2177 (D2177N) (23), was present in 7 of the 167 AMD patients and in only 1 of 220 controls, which is a significant difference by Fisher`s exact test (P 5 0.023). Login to comment
96 Mutation AMD (n 5167) STGD (n 5 98) General population (n 5 220) E471K 2 (1.2%) NA 0 (0%) R1129L 1 (0.6%) 0 (0%)* 0 (0%) T1428M 1 (0.6%) 0 (0%) 0 (0%) R1517S 1 (0.6%) 0 (0%) 0 (0%) I1562T 2 (1.2%) 0 (0%) 0 (0%) G1578R 1 (0.6%) 0 (0%) 0 (0%) 519611G 3 A 1 (0.6%) 0 (0%) 0 (0%) R1898H 1 (0.6%) 4 (4%) 0 (0%) G1961E 6 (3.6%) 8 (8%) 0 (0%) L1970F 1 (0.6%) 0 (0%) 0 (0%) 6519D11bp 1 (0.6%)ߤ 1 (1%)ߤ 0 (0%) D2177N 7 (4.2%) 0 (0%) 1 (0.45%) 6568DC 1 (0.6%) 0 (0%) 0 (0%) Totals 26 (16%) 13 (13%) 1 (0.45%) *A substitution to a different amino acid (R1129C) was detected in one STGD1 patient. Login to comment

[hide] ABCA4 gene screening by next-generation sequencing... Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, Tsubota K, Webster AR, Moore AT, Allikmets R, Michaelides M
ABCA4 gene screening by next-generation sequencing in a British cohort.
Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570., [PMID:23982839]

Abstract [show]
PURPOSE: We applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations. METHODS: We identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis. RESULTS: Of the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease-causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice-site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals. CONCLUSIONS: Application of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost-efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies.

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55 1 c.161G>A p.C54Y DC c.2297G>T p.G766V DC 2 2 c.223T>G p.C75G DC c.5088C>G p.S1696R DC 2 3 c.740A>C p.N247T DC c.1433T>C p.I478T B c.2345G>A p.W782* DC 2 4 c.768G>T Splice site DC 1 5 c.1222C>T p.R408* DC c.2568C>A p.Y856* DC 2 6 c.1804C>T p.R602W DC c.859-9T>C Splice site PDC 2 7 c.1805G>A p.R602Q DC c.5113C>T p.R1705W DC 2 8 c.1922G>C p.C641S DC 1 9 c.1957C>T p.R653C DC 1 10 c.1957C>T p.R653C DC 1 11 c.2588G>C p.G863A DC c.655A>T p.R219* DC 2 Allele 2 (p.R219*) was APEX-false-negative 12 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 13 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 14 c.2588G>C p.G863A DC 1 15 c.2588G>C p.G863A DC 1 16 c.2894A>G p.N965S DC c.3322C>T p.R1108C DC 2 Allele 2 (p.R1108C) was APEX-false-negative 17 c.3064G>A p.E1022K DC c.6729&#fe;4_&#fe;18delAGTTGGCCCTGGGGC Splice site DC 2 18 c.3064G>A p.E1022K DC 1 19 c.3208_3209insGT p.S1071fs DC c.2942C>T p.P981L DC c.6529G>A p.D2177N B 2 20 c.3208_3209insGT p.S1071fs DC c.1519G>T p.D507Y DC 2 21 c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 2 22 c.3208_3209insGT p.S1071fs DC 1 23 c.3292C>T p.R1098C DC c.3299T>A p.I1100N DC 2 24 c.3322C>T p.R1108C DC c.4978delC p.L1661* DC 2 25 c.3386G>A p.R1129H DC c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 3 Allele 2 (p.S1071fs) was APEX false-negative and allele 1 (p.R1129H) was NGS false-negative 26 c.4139C>T p.P1380L DC c.3191-1G>T Splice site DC 2 27 c.4139C>T p.P1380L DC c.3398T>C p.I1133T PDC 2 28 c.4139C>T p.P1380L DC c.4070C>A p.A1357E DC 2 29 c.4139C>T p.P1380L DC c.4773G>C Splice site DC 2 30 c.4139C>T p.P1380L DC 1 31 c.4139C>T p.P1380L DC 1 32 c.4139C>T p.P1380L DC 1 33 c.4234C>T p.Q1412* DC 1 34 c.4319T>C p.F1440S DC 1 35 c.4328G>A p.R1443H DC c.180delG p.M61fs DC 2 36 c.4469G>A p.C1490Y DC c.1726G>C p.D576H DC 2 37 c.4469G>A p.C1490Y DC 1 38 c.4537_4538insC p.Q1513fs DC c.5578C>T p.R1860W DC 2 Allele 1 (p.Q1513fs) was NGS-false-negative 39 c.4577C>T p.T1526M DC 1 T ABLE 2. Continued Pt Allele 1 Detected by APEX Allele 2 Detected by NGS Allele 3 Detected by NGS Total N of DC Variants Comments DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho. Login to comment
63 Hum Var Score (0-1) Site Wt CV Mt CV CV % Variation 30 c.4537_4538insC p.G1513fs 1 38 [ Briggs CE, et al. 19 ND False-negative in NGS in patient 38 31 c.4577C>T p.T1526M 1 39 [ [ Lewis RA, et al. 11 Del. 0.00 PRD 0.910 No change ND db SNP (rs61750152) 33 c.4685T>C p.I1562T 1 71 [ [ Yatsenko, et al. 13 Tol. NA PRD 0.783 No change ND Benign 33 c.4715C>T p.T1572M 1 79 [ [ Pang CP and Lamm DS 23 Del. 0.02 B 0.326 No change ND db SNP (rs185093512) Benign 35 c.4926C>G p.S1642R 1 40 [ [ Birch DG, et al. 22 Tol. 0.68 B 0.116 No change ND db SNP (rs61753017) 35 c.4956T>G p.Y1652* 1 41 [ [ Fumagalli A, et al. 16 ND db SNP (rs61750561) IVS35 c.5018&#fe;2T>C Splice site 1 42 [ [ APEX Don. 81.2 54.3 WT site broken (33.07) ND 36 c.5113C>T p.R1705W 1 7 [ Ernest PJ, et al. 26 Del. NA PRD 0.996 Don. 46.5 73.3 No change ND IVS38 c.5461-10T>C 8 43, 44, 45, 46, 47, 48, 49, 50 [ [ Briggs CE, et al. 19 No change 3/13006 db SNP (rs1800728) IVS39 c.5585-1G>A Splice site 1 51 [ [ Shroyer NF, et al. 21 Acc. 86.3 57.4 WT site broken (33.53) ND IVS40 c.5714&#fe;5G>A Splice site 1 52 [ [ Cremers FP, et al. 8 Don. 85.5 73.3 Wild type site broken (14.23) ND 42 c.5882G>A p.G1961E 7 53, 54, 55, 56, 57, 58, 59 [ [ Lewis RA, et al. 11 Del. 0.00 PRD 0.998 No change 41/13006 db SNP (rs1800553) 44 c.6079C>T p.L2027F 4 60, 61, 62, 63 [ [ Lewis RA, et al. 11 Del. 0.00 PRD 1.000 No change 4/13006 db SNP (rs61751408) 44 c.6089G>A p.R2030Q 1 64 [ [ Lewis RA, et al. 11 Del. 0.00 PRD 0.995 No change 8/13006 db SNP (rs61750641) 46 c.6320G>A p.R2107H 2 72, 73 [ [ Fishman GA, et al. 15 Del. 0.04 PRD 0.999 No change 91/13006 db SNP (rs62642564) Benign 47 c.6445C>T p.R2149* 1 65 [ [ Lewis RA, et al. 14 1/13006 db SNP (rs61750654) 48 c.6529G>A p.D2177N 1 19 [ Rivera A, et al. 17 Tol. 0.41 B 0.004 No change 116/13006 db SNP (rs1800555) Benign 48 c.6709A>C p.T2237P 1 66 [ [ APEX Del. NA POD 0.719 No change ND IVS48 c.6729&#fe;4_ &#fe;18del AGTTGGCCCTGGGGC Splice site 1 17 [ Littink KW, et al. 28 NA ND Splice-site alteration (described as splice site) includes the change expected to affect splicing, for example, when the splice donor or splice acceptor site is changed, and the change that might affect splicing, for example, changes close to the splice donor or splice acceptor site, or in the first or last nucleotide of an exon. SIFT (version 4.0.4) results are reported to be tolerant if tolerance index is ߥ0.05 or deleterious if tolerance index is <0.05. Login to comment
115 Of the 9 previously reported variants that were detected by NGS, there were 4 null variants (2 nonsense and 2 splice-site alterations); 4 disease-causing missense variants, with deleterious or damaged protein function predicted by SIFT and Polyphen2; and one benign missense variant (p.D2177N, Table 3). Login to comment

[hide] Molecular diagnostic testing by eyeGENE: analysis ... Invest Ophthalmol Vis Sci. 2014 Jul 31;55(9):5510-21. doi: 10.1167/iovs.14-14359. Alapati A, Goetz K, Suk J, Navani M, Al-Tarouti A, Jayasundera T, Tumminia SJ, Lee P, Ayyagari R
Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss.
Invest Ophthalmol Vis Sci. 2014 Jul 31;55(9):5510-21. doi: 10.1167/iovs.14-14359., [PMID:25082885]

Abstract [show]
PURPOSE: To analyze the genetic test results of probands referred to eyeGENE with a diagnosis of hereditary maculopathy. METHODS: Patients with Best macular dystrophy (BMD), Doyne honeycomb retinal dystrophy (DHRD), Sorsby fundus dystrophy (SFD), or late-onset retinal degeneration (LORD) were screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5, respectively. Patients with pattern dystrophy (PD) were screened for mutations in PRPH2, BEST1, ELOVL4, CTRP5, and ABCA4; patients with cone-rod dystrophy (CRD) were screened for mutations in CRX, ABCA4, PRPH2, ELOVL4, and the c.2513G>A p.Arg838His variant in GUCY2D. Mutation analysis was performed by dideoxy sequencing. Impact of novel variants was evaluated using the computational tool PolyPhen. RESULTS: Among the 213 unrelated patients, 38 had BMD, 26 DHRD, 74 PD, 8 SFD, 6 LORD, and 54 CRD; six had both PD and BMD, and one had no specific clinical diagnosis. BEST1 variants were identified in 25 BMD patients, five with novel variants of unknown significance (VUS). Among the five patients with VUS, one was diagnosed with both BMD and PD. A novel EFEMP1 variant was identified in one DHRD patient. TIMP3 novel variants were found in two SFD patients, PRPH2 variants in 14 PD patients, ABCA4 variants in four PD patients, and p.Arg838His GUCY2D mutation in six patients diagnosed with dominant CRD; one patient additionally had a CRX VUS. ABCA4 mutations were identified in 15 patients with recessive CRD. CONCLUSIONS: Of the 213 samples, 55 patients (26%) had known causative mutations, and 13 (6%) patients had a VUS that was possibly pathogenic. Overall, selective screening for mutations in BEST1, PRPH2, and ABCA4 would likely yield the highest success rate in identifying the genetic basis for macular dystrophy phenotypes. Because of the overlap in phenotypes between BMD and PD, it would be beneficial to screen genes associated with both diseases.

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39 Mutations and Unknown Variants Detected in Patients With Central Vision Loss Patient Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Molecular Diagnosis Late-onset retinal degeneration NA CTRP5 NA NA NA NA NA NA Sorsby fundus dystrophy Patient 1 TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 Positive Patient 2 TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 Positive Patient 3 TIMP3 5 c.610A>T p.Ser204Cys Het Mut Positive Doyne honeycomb dystrophy Patient 1 EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut Positive Patient 2 EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut Positive Patient 3 EFEMP1 IVS10 c.IVS10-14C>T None Het vAR/us NA NA Unconfirmed Best macular dystrophy Patient 1 BEST1 2 c.28G>A p.Ala10Thr Het Mut Positive Patient 2 BEST1 2 c.47C>T p.Ser16Phe Het Mut Positive Patient 3 BEST1 2 c.72G>T p.Trp24Cys Het Mut Positive Patient 4 BEST1 3 c.240C>A p.Phe80Leu Het Mut Positive Patient 5 BEST1 3 c.240C>A p.Phe80Leu Het Mut Positive Patient 6 BEST1 4 c.248G>C p.Gly83Ala Het vAR/us Probably damaging 1 Positive Patient 7 BEST1 4 c.277T>C p.Trp93Arg Het vAR/us Probably damaging 1 Positive Patient 8 BEST1 4 c.279G>C p.Trp93Cys Het Mut Positive Patient 9 BEST1 6 c.652C>T p.Arg218Cys Het Mut Positive Patient 10 BEST1 6 c.652C>T p.Arg218Cys Het Mut Positive Patient 11 BEST1 6 c.680A>G p.Tyr227Cys Het Mut Positive Patient 12 BEST1 6 c.741G>A p.Arg218His Het Mut Positive Patient 13 BEST1 6 c.741G>A p.Arg218His Het Mut Positive Patient 14 BEST1 7 c.727G>A p.Ala243Thr Het Mut Positive Patient 15 BEST1 7 c.727G>A p.Ala243Thr Het Mut Positive Patient 16 BEST1 7 c.728C>T p.Ala243Val Het Mut Positive Patient 17 BEST1 7 c.728C>T p.Ala243Val Het Mut Positive Patient 18 BEST1 8 c.880C>T p.Leu294Phe Het vAR/us Probably damaging 1 Positive Patient 19 BEST1 8 c.887A>G p.Asn296Ser Het Mut Positive Patient 20 BEST1 8 c.903T>G p.Asp301Glu Het Mut Positive Patient 21 BEST1 8 c.903T>G p.Asp301Glu Het Mut Positive Patient 22 BEST1 8 c.910G>A p.Asp304Asn Het Mut Positive Patient 23 BEST1 8 c.925T>C p.Trp309Arg Het vAR/us Probably damaging 1 Positive Patient 24 BEST1 8 c.929T>C p.Ile310Thr Het Mut Positive Patient 25, case 3 BEST1 4 c.250T>G p.Phe84Val Het vAR/us Probably damaging 1 Positive Pattern dystrophy Patient 1 ABCA4 6 c.634C>T p.Arg212Cys Het Mut Positive ABCA4 30 c.4469G>A p.Cys1490Tyr Het Mut Patient 2 ABCA4 17 c.2588G>C p.Gly863Ala Het Mut Unconfirmed Patient 3 ABCA4 IVS26 c.3862&#fe;3A>G Abnormal splicing Het vAR/us Unconfirmed Patient 4 PRPH2 1 c.271T>A p.Tyr91Asn Het vAR/us Probably damaging 0.909 Positive PRPH2 1 c.310-313del(AT) p.Ile104Val Het Mut Patient 5, case 6 PRPH2 1 c.422A>G p.Tyr141Cys Het Mut Positive Patient 6 PRPH2 1 c.422A>G p.Tyr141Cys Het Mut Positive Patient 7 PRPH2 1 c.515G>A p.Arg172Gln Het Mut Positive Patient 8 PRPH2 2 c.583C>T p.Arg195Stop Het Mut Positive Patient 9 PRPH2 2 c.629C>G p.Pro210Arg Het Mut Positive Patient 10 PRPH2 2 c.635G>C p.Ser212Thr Het Mut Positive Patient 11 PRPH2 2 c.683C>T p.Thr228Ile Het Mut Positive Patient 12 PRPH2 2 c.708C>G p.Tyr236Stop Het Mut Positive Patient 13, case 4 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive TABLE 2. Continued Patient Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Molecular Diagnosis Patient 14 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 15 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 16 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 17, case 2 ABCA4 IVS38 c.5461-10T>C None Het Mut Unconfirmed Patient 18 PRPH2 2 c.584G>A p.Arg195Gln Het vAR/us Probably damaging 1 Positive Cone-rod dystrophy Patient 1, dominant GUCY2D 13 c.2512C>T p.Arg838Cys Het Mut Positive Patient 2, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 3, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 4, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 5, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive CRX 3 c.607T>C p.Ser213Pro Het vAR/us Probably damaging 0.999 Patient 6, recessive ABCA4 2 c.156T>G p.His52Gln Het vAR/us Probably damaging 0.998 Positive ABCA4 3 c.161G>A p.Cys54Tyr Het Mut ABCA4 28 c.4169T>C p.Leu1390Pro Het Mut Patient 7, recessive ABCA4 16 c.2385C>T p.Ser795Arg Het vAR/us Probably damaging 0.99 Positive ABCA4 IVS40 c.5714&#fe;5G>A Splice Het Mut Patient 8, recessive ABCA4 42 c.5882G>A p.Gly1961Glu Het Mut Positive ABCA4 45 c.6221G>T p.Gly2074Val Het vAR/us Probably damaging 1 Patient 9, recessive ABCA4 IVS42 c.5898&#fe;1G<A Splice Het Mut Positive ABCA4 IVS42 c.5899-2delA Splice Het Mut Patient 10, recessive ABCA4 5 c.559C>T p.Arg187Cys Het Mut Positive ABCA4 40 c.5645T>C p.Met1882Thr Het Mut Patient 11, recessive ABCA4 6 c.768G>T p.Val256Val (abnlspl) Het Mut Positive ABCA4 31 c.4577C>T p.Thr1526Met Het Mut Patient 12, recessive ABCA4 12 c.1622T>C p.Leu541Pro Het Mut Positive ABCA4 21 c.3113C>T p.Ala1038Val Het Mut ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut ABCA4 22 c.3322C>T p.Arg1108Cys Het Mut Patient 13, recessive ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut Positive ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut Patient 14, recessive ABCA4 13 c.1927G>A p.Val643Met Het Mut Positive ABCA4 24 c.3602T>G p.Leu1201Arg Het Mut ABCA4 36 c.5186T>C p.Leu1729Pro Het Mut Patient 15, recessive ABCA4 23 c.3364G>A p.Glu1122Lys Het Mut Positive ABCA4 48 c.6529G>A p.Asp2177Asn Het Mut Patient 16, recessive ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut Positive ABCA4 28 c.4222T>C p.Trp1408Arg Het Mut Patient 17, recessive ABCA4 11 c.1532G>A p.Arg511His Het Mut Unconfirmed Patient 18, recessive ABCA4 27 c.3899G>A p.Arg1300Gln Het vAR/us Benign 0.143 Unconfirmed Patient 19, recessive ABCA4 13 c.1933G>A p.Asp645Asn Het Mut Unconfirmed Patient 20, recessive ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut Unconfirmed Patient 21, recessive ABCA4 IVS7 c.859-9T>C Unknown Hom vAR/us NA NA Unconfirmed Molecular Diagnostic Testing by eyeGENE IOVS j September 2014 j Vol. 55 j No. 9 j were screened for the p.Arg838His mutation in GUCY2D, and mutations in the CRX, ELOVL4, PRPH2, and/or ABCA4 genes. 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116 Mutations or Unknown Variants Detected in Patients With Central Vision Loss Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Frequency* Variant ID Late-onset retinal degeneration CTRP5 NA NA NA NA NA NA NA NA NA Sorsby fundus dystrophy TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 2 TIMP3 5 c.610A>T p.Ser204Cys Het Mut 1 CM941325/ rs137853298 Doyne honeycomb dystrophy EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut 2 CM990504 EFEMP1 IVS10 c.IVS10-14C>T None Het vAR/us NA NA 1 Best macular dystrophy BEST1 2 c.28G>A p.Ala10Thr Het Mut 1 CM982017 BEST1 2 c.47C>T p.Ser16Phe Het Mut 1 CM010520 BEST1 2 c.72G>T p.Trp24Cys Het Mut 1 CM982018 BEST1 3 c.240C>A p.Phe80Leu Het Mut 2 CM004423 BEST1 4 c.248G>C p.Gly83Ala Het vAR/us Probably damaging 1 1 BEST1 4 c.277T>C p.Trp93Arg Het vAR/us Probably damaging 1 1 BEST1 4 c.279G>C p.Trp93Cys Het Mut 1 rs28940273/ CM982021 BEST1 6 c.652C>T p.Arg218Cys Het Mut 2 CM982023 BEST1 6 c.680A>G p.Tyr227Cys Het Mut 1 CM982024 BEST1 6 c.741G>A p.Arg218His Het Mut 2 CM003486 BEST1 7 c.727G>A p.Ala243Thr Het Mut 2 CM004434 BEST1 7 c.728C>T p.Ala243Val Het Mut 2 rs28940570/ CM00841 BEST1 8 c.880C>T p.Leu294Phe Het vAR/us Probably damaging 1 1 BEST1 8 c.887A>G p.Asn296Ser Het Mut 1 CM010524 BEST1 8 c.903T>G p.Asp301Glu Het Mut 2 CM991243 BEST1 8 c.910G>A p.Asp304Asn Het Mut 1 CM024219 BEST1 8 c.925T>C p.Trp309Arg Het vAR/us Probably damaging 1 1 BEST1 8 c.929T>C p.Ile310Thr Het Mut 1 CM000843 BEST1 4 c.250T>G p.Phe84Val Het vAR/us Probably damaging 1 1 Pattern dystrophy ABCA4 6 c.634C>T p.Arg212Cys Het Mut 1 rs61750200 ABCA4 17 c.2588G>C p.Gly863Ala Het Mut 1 CM970003/ rs76157638 ABCA4 IVS26 c.3862&#fe;3A>G Abnormal splicing Het vAR/us 1 NA ABCA4 30 c.4469G>A p.Cys1490Tyr Het Mut 1 CM990056/ rs61751402 ABCA4 IVS38 c.5461-10T>C None Het Mut 1 CS057513 PRPH2 1 c.271T>A p.Tyr91Asn Het vAR/us Probably damaging .909 1 PRPH2 1 c.310-313del(AT) p.Ile104Val Het Mut 1 NA/Deletion PRPH2 1 c.422A>G p.Tyr141Cys Het Mut 2 CM010125/ rs61755781 PRPH2 1 c.515G>A p.Arg172Gln Het Mut 1 CM930637/ rs61755792 PRPH2 2 c.583C>T p.Arg195Stop Het Mut 1 CM032999 PRPH2 2 c.629C>G p.Pro210Arg Het Mut 1 CM941210 PRPH2 2 c.635G>C p.Ser212Thr Het Mut 1 CM971289/ rs61755801 PRPH2 2 c.683C>T p.Thr228Ile Het Mut 1 TMP_ESP_6_ 42672248 PRPH2 2 c.708C>G p.Tyr236Stop Het Mut 1 rs61755813 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut 4 CS010139 PRPH2 2 c.584G>A p.Arg195Gln Het vAR/us Probably damaging 1 1 TABLE 3. Continued Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Frequency* Variant ID Cone-rod dystrophy ABCA4 2 c.156T>G p.His52Gln Het vAR/us Probably damaging 0.998 1 ABCA4 3 c.161G>A p.Cys54Tyr Het Mut 1 CM990012/ rs150774447 ABCA4 28 c.4169T>C p.Leu1390Pro Het Mut 1 CM014810/ rs61752430 ABCA4 16 c.2385C>T p.Ser795Arg Het vAR/us Probably damaging 0.99 1 ABCA4 IVS40 c.5714&#fe;5G>A Splice Het Mut 1 CS982057 ABCA4 27 c.3899G>A p.Arg1300Gln Het vAR/us Benign 0.143 1 ABCA4 32 c.4661A>G p.Glu1554Gly Het vAR/us Benign 0.326 1 ABCA4 30 c.4383G>A p.Trp1461Stop Het Mut 1 Stop/NA ABCA4 IVS38 c.5461-10T>C None Het Mut NA NA 2 CS057513 ABCA4 22 c.3259G>A p.Glu1087Lys Het Mut 1 CM970008/ rs61751398 ABCA4 42 c.5882G>A p.Gly1961Glu Het Mut 2 CM970016/ rs1800553 ABCA4 45 c.6221G>T p.Gly2074Val Het vAR/us Probably damaging 1 1 ABCA4 IVS42 c.5898&#fe;1G<A Splice Het Mut 1 CS011524 ABCA4 IVS42 c.5899-2delA Splice Het Mut 1 rs3112831 CRX 3 c.607T>C p.Ser213Pro Het vAR/us Probably damaging 0.999 1 ABCA4 5 c.559C>T p.Arg187Cys Het Mut 1 COSM913472 ABCA4 40 c.5645T>C p.Met1882Thr Het Mut 1 rs4147830 ABCA4 6 c.768G>T p.Val256Val (abnlspl) Het Mut 1 CM990057/ rs61750152 ABCA4 31 c.4577C>T p.Thr1526Met Het Mut 1 rs62645944 ABCA4 11 c.1532G>A p.Arg511His Het Mut 1 rs140482171 ABCA4 12 c.1622T>C p.Leu541Pro Het Mut 1 CM990022/ rs61751392 ABCA4 21 c.3113C>T p.Ala1038Val Het Mut 1 CM970006/ rs61751374 ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut 2 CM990022/ rs61751392 ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut 2 CM970006/ rs61751374 ABCA4 22 c.3322C>T p.Arg1108Cys Het Mut 1 CM990039/ rs61750120 ABCA4 13 c.1927G>A p.Val643Met Het Mut 1 CM014293/ rs61749417/ rs143548435 ABCA4 24 c.3602T>G p.Leu1201Arg Het Mut 1 CM990042/ rs61750126 ABCA4 36 c.5186T>C p.Leu1729Pro Het Mut 1 CM990062/ rs61750567 ABCA4 13 c.1933G>A p.Asp645Asn Het Mut 1 rs617494181933 ABCA4 23 c.3364G>A p.Glu1122Lys Het Mut 1 CM990041 ABCA4 48 c.6529G>A p.Asp2177Asn Het Mut 1 CM970023/ rs1800555 ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut 2 CM983728/ rs61751404 ABCA4 28 c.4222T>C p.Trp1408Arg Het Mut 1 CM990048/ rs61750135 GUCY2D 13 c.2512C>T p.Arg838Cys Het Mut 1 rs61750172 GUCY2D 13 c.2513G>A p.Arg838His Het Mut 5 CM012606/ rs61750173 ABCA4 IVS7 c.859-9T>C Unknown Hom vAR/us NA NA 1 ABCA4 42 c.5882G>A p.Gly1961Glu Hom Mut 1 CM970016/ rs1800553 ABCA4 43 c.5917delG Deletion Hom Mut 1 RISN_ABCR: c.5917delG Molecular Diagnostic Testing by eyeGENE IOVS j September 2014 j Vol. 55 j No. 9 j Six patients with late-onset retinal pathology and drusen had well-characterized clinical data. 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[hide] Associations of the G1961E and D2177N variants in ... Gene. 2015 Aug 1;567(1):51-7. doi: 10.1016/j.gene.2015.04.068. Epub 2015 Apr 25. Zhang R, Wang LY, Wang YF, Wu CR, Lei CL, Wang MX, Ma L
Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration.
Gene. 2015 Aug 1;567(1):51-7. doi: 10.1016/j.gene.2015.04.068. Epub 2015 Apr 25., [PMID:25921964]

Abstract [show]
OBJECTIVE: The aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. DESIGN AND METHODS: All eligible studies published up to October 2014 were obtained from MEDLINE, EMBASE, and ISI Web of Science. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the strength of this association. RESULTS: Twenty-four studies enrolling 4580 AMD cases and 5180 controls were identified. Both G1961E (OR = 3.22, 95% CI: 1.74-5.95) and D2177N (OR = 2.36, 95% CI: 1.41-3.93) variations showed significant associations with increased risk of AMD. In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR = 4.31, 95% CI: 1.90-9.73), while no association was demonstrated in Europeans. For Asians, no carriers of the risk factor A allele in either variant were detected in any of AMD patients and control subjects. CONCLUSIONS: Significant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. However, large-scale studies are still required to further validate these findings in different ethnicities.

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0 Research paper Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration Rui Zhang a,1 , Li-Yuan Wang a,1 , Ya-Feng Wang a , Chang-Rui Wu b , Chun-Ling Lei c , Ming-Xu Wang a, Ìe;, Le Ma a, Ìe; a School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China b The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China c The Fourth Hospital of Xi'an, Xi'an Jiaotong University, Xi'an, China a b s t r a c t a r t i c l e i n f o Article history: Received 22 January 2015 Received in revised form 21 April 2015 Accepted 23 April 2015 Available online 25 April 2015 Keywords: Age-related macular degeneration ABCA4 Polymorphism Objective: The aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. Login to comment
4 Both G1961E (OR = 3.22, 95% CI: 1.74-5.95) and D2177N (OR = 2.36, 95% CI: 1.41-3.93) variations showed significant associations with increased risk of AMD. Login to comment
5 In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR = 4.31, 95% CI: 1.90-9.73), while no association was demonstrated in Europeans. Login to comment
7 Conclusions: Significant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. Login to comment
20 Two common sequence variants in ABCA4, G1961E (c.5882G N A) and D2177N (c.6529G N A) accounted for over half of the reported disease-associated variants; many investigators have assessed the role of ABCA4 in AMD through these two mutations (Allikmets et al., 1997; Allikmets, 2000; Souied et al., 2000). Login to comment
29 We performed a meta-analysis based on published data to clarify the contributions of G1961E and D2177N sequence variants towards the risk of AMD for different populations. Login to comment
38 First, an initial review of the identified abstracts and titles in all of the relevant articles was conducted to exclude those studies that did not address the association between G1961E or D2177N mutations and the risk of AMD. Login to comment
53 Statistical methods An odds ratio (OR) with a corresponding 95% confidence interval (CI) was used to assess the strength of the association between each variant and susceptibility of AMD under an allelic model (G1961E: c.5882G N A and D2177N: c.6529G N A). Login to comment
86 D2177N variation and AMD risk Similar to the G1961E variant, all of the included studies reported data for the frequency of the D2177N variation in cases and controls. Login to comment
89 All of the D2177N variant occurrences were in the heterozygous state. Login to comment
91 Overall, the frequency of the risk factor A allele was higher in AMD patients than in the controls (1.66% vs. 0.58%), and the fixed effects pooled OR (A vs. T: OR = 2.36, 95% CI: 1.41-3.93; Fig. 3) estimated an elevated risk of AMD in carriers of the D2177N variant. Login to comment
93 The frequency of the A allele for D2177N in control subjects was noted to be significantly higher in Europeans compared with Americans (1.01% vs. 0.32%, P = 0.037). Login to comment
98 Discussion In the current study, we evaluated the effects of the G1961E and D2177N variants in ABCA4 on AMD susceptibility based on data from 24 case-control studies. Login to comment
100 Furthermore, the subgroup analyses indicated that the significant relationship between the D2177N variant and AMD was only detected in Americans, but not in Europeans. Login to comment
107 Two common coding polymorphisms located in ABCA4, G1961E and D2177N have been considered to be related to the risk for AMD. Login to comment
113 Sun et al. suggested that the G1961E protein and the D2177N protein could significantly decrease ATPase activity by retinal compared with the wild-type ABCA4 protein (Sun et al., 1999). Login to comment
117 First author and year Country Variation location Number Source of control Diagnostic criteria Classification criteria Genotyping methods Quality scorea Cases Controls De La Paz et al. (1999) USA G1961E, D2177N 169 56 HB Fundus photography ICGS SSCP + HA 8 Kuroiwa et al. (1999) Japan G1961E, D2177N 80 100 HB Fundus photography ICGS PCR + SSCP 8 McNeill et al. (2000) USA G1961E, D2177N 177 150 PB NR NR NR 4 Souied et al. (2000) France G1961E, D2177N 52 90 PB Fundus photography ICGS SSCP 7 Allikmets (2000) USA G1961E, D2177N 229 200 PB NR NR NR 7 USA G1961E, D2177N 101 100 PB NR NR NR 7 USA G1961E, D2177N 103 158 PB NR NR NR 6 Germany G1961E, D2177N 200 100 PB NR NR NR 7 Holland G1961E, D2177N 83 168 PB NR NR NR 6 USA G1961E, D2177N 115 100 PB NR NR NR 7 Italy G1961E, D2177N 92 171 PB NR NR NR 6 Spain G1961E, D2177N 36 34 PB NR NR NR 7 Sweden G1961E, D2177N 102 100 PB NR NR NR 6 UK G1961E, D2177N 90 20 PB NR NR NR 7 France G1961E, D2177N 67 107 PB NR NR NR 6 Rivera et al. (2000) Germany G1961E, D2177N 200 220 PB Fundus photography ICGS DGGE + DHPLC + SSCP 8 Fuse et al. (2000) Japan G1961E, D2177N 25 40 PB Fundus photography ICGS PCR 7 Webster et al. (2001) USA G1961E, D2177N 182 96 HP Fundus photography ICGS SSCP 7 Guymer et al. (2001) USA G1961E, D2177N 304 408 PB Fundus photography ICGS PCR 8 Australia G1961E, D2177N 201 187 PB Fundus photography ICGS PCR 8 Switzerland G1961E, D2177N 39 94 PB Fundus photography ICGS PCR 8 Bernstein et al. (2002) USA G1961E, D2177N 167 220 PB Fundus photography AREDS direct sequencing 7 Schmidt et al. (2003) USA G1961E, D2177N 165 59 PB Fundus photography ICGS DHPLC + PCR 8 Baum et al. (2003) China G1961E, D2177N 140 95 HP Fundus photography NR PCR 6 AREDS, Age-Related Eye Disease Study; DGGE, denaturing gradient gel electrophoresis; DHPLC, denaturing high performance liquid chromatography; HA, heteroduplex analysis; HP, hospital-based; ICGS, International Classification and Grading System; NR, not reported; PB, population-based; PCR, polymerase chain reaction; SSCP, single-strand conformation polymorphism. Login to comment
122 In the present study, no significant relationship between the D2177N variant and AMD risk was found in Europeans, which differed significantly from Americans. Login to comment
124 The results of our study showed that the frequency of the A allele for D2177N in control subjects was significantly higher in Europeans compared to Americans, which also supported the hypothesis that Americans were more likely than Europeans to Table 2 Stratified analysis of the association between the G1961E and D2177N variations and AMD. Login to comment
125 Subgroup G1961E D2177N N OR (95% CI) I2 (%) Pz Ph N OR (95% CI) I2 (%) Pz Ph Country of origin Europe 10 2.81 (1.14, 6.69) 0 0.82 0.60 10 1.18 (0.54, 2.57) 0 0.92 0.04 United States 10 3.89 (1.59, 9.56) 0 0.67 10 4.31 (1.90, 9.73) 0 0.78 Asia 3 NA NA NA 3 NA NA NA Australia 1 1.86 (0.17, 20.69) NA NA 1 2.33 (0.45, 12.13) NA NA Source of controls Population-based 20 3.31 (1.77, 6.18) 0 0.89 0.54 20 2.37 (1.40, 4.02) 0 0.68 0.58 Hospital-based 4 1.59 (0.06, 39.31) NA NA 4 2.12 (0.25, 18.30) 0 0.83 Age of case (years) b75 3 NA NA NA NP 3 NA NA NA NP ࣙ75 4 2.31 (0.77, 6.93) 0 0.91 4 1.46 (0.60, 3.53) 0 0.87 Classification criteria ICGS 10 2.11 (0.78, 6.28) 0 0.91 NP 10 1.54 (0.66, 3.59) 0 0.93 0.18 AREDS 1 17.11 (0.96, 305.92) NA NA 1 9.22 (1.12, 75.68) NA NA Genotyping methods PCR 5 2.39 (0.57, 10.18) 0 0.76 0.38 5 2.05 (0.61, 6.92) 0 0.82 0.33 SSCP 2 1.59 (0.06, 39.31) NA NA 2 2.64 (0.13, 55.62) NA NA Direct sequencing 1 17.11 (0.96, 305.92) NA NA 1 9.22 (1.12, 75.68) NA NA Quality scorea High 17 2.63 (1.27, 5.43) 0 0.88 0.38 17 1.96 (1.08, 3.54) 0 0.82 0.26 Moderate 6 5.47 (1.54, 19.36) 0 0.60 6 3.20 (1.05, 9.76) 0 0.42 Low 1 4.19 (0.20, 88.00) NA NA 1 9.33 (0.51, 170.05) NA NA AREDS, Age-Related Eye Disease Study; ICGS, International Classification and Grading System; OR, odds ratio; CI, confidence interval; PCR, polymerase chain reaction; Pz, P for Z test; Ph, P for between-study heterogeneity; NA, not applicable; NP, meta-regression was not possible. Login to comment
127 Fig. 3. Forest plot on the association between the D2177N variation and AMD risk under the allelic model (A vs. G). Login to comment
131 Inconsistencies in the characteristics of the populations studied might somewhat affect the findings for the D2177N variant and AMD risk. Login to comment
134 First, the relatively small sample sizes might reduce the statistical power to assess the association between G1961E and D2177N variations and the susceptibility to AMD. Login to comment
142 In conclusion, the present meta-analysis demonstrated that the variants of G1961E and D2177N in ABCA4 were significantly associated with increased risk of AMD, specifically for Americans. Login to comment

[hide] Quantitative Fundus Autofluorescence and Optical C... Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371. Duncker T, Stein GE, Lee W, Tsang SH, Zernant J, Bearelly S, Hood DC, Greenstein VC, Delori FC, Allikmets R, Sparrow JR
Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.
Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371., [PMID:26551331]

Abstract [show]
PURPOSE: To assess whether carriers of ABCA4 mutations have increased RPE lipofuscin levels based on quantitative fundus autofluorescence (qAF) and whether spectral-domain optical coherence tomography (SD-OCT) reveals structural abnormalities in this cohort. METHODS: Seventy-five individuals who are heterozygous for ABCA4 mutations (mean age, 47.3 years; range, 9-82 years) were recruited as family members of affected patients from 46 unrelated families. For comparison, 57 affected family members with biallelic ABCA4 mutations (mean age, 23.4 years; range, 6-67 years) and two noncarrier siblings were also enrolled. Autofluorescence images (30 degrees , 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Horizontal SD-OCT scans through the fovea were obtained and the thicknesses of the outer retinal layers were measured. RESULTS: In 60 of 65 carriers of ABCA4 mutations (age range, 9-60), qAF levels were within normal limits (95% confidence level) observed for healthy noncarrier subjects, while qAF levels of affected family members were significantly increased. Perifoveal fleck-like abnormalities were observed in fundus AF images in four carriers, and corresponding changes were detected in the outer retinal layers in SD-OCT scans. Thicknesses of the outer retinal layers were within the normal range. CONCLUSIONS: With few exceptions, individuals heterozygous for ABCA4 mutations and between the ages of 9 and 60 years do not present with elevated qAF. In a small number of carriers, perifoveal fleck-like changes were visible.

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298 Zhang R, Wang LY, Wang YF, et al. Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration. Login to comment