ABCMdb

ABCA4 p.Arg943Gln

ClinVar:	c.2827C>G , p.Arg943Gly ? , not provided c.2828G>A , p.Arg943Gln ? , Conflicting interpretations of pathogenicity, not provided, risk factor c.2827C>T , p.Arg943Trp ? , not provided
Predicted by SNAP2:	A: D (75%), C: D (75%), D: D (80%), E: D (75%), F: D (80%), G: D (80%), H: D (66%), I: D (91%), K: N (66%), L: D (75%), M: D (75%), N: D (66%), P: D (75%), Q: D (80%), S: D (85%), T: D (59%), V: D (75%), W: D (95%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D,

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[hide] Further associations between mutations and polymor... Invest Ophthalmol Vis Sci. 2011 Aug 5;52(9):6206-12. Print 2011 Aug. Aguirre-Lamban J, Gonzalez-Aguilera JJ, Riveiro-Alvarez R, Cantalapiedra D, Avila-Fernandez A, Villaverde-Montero C, Corton M, Blanco-Kelly F, Garcia-Sandoval B, Ayuso C
Further associations between mutations and polymorphisms in the ABCA4 gene: clinical implication of allelic variants and their role as protector/risk factors.
Invest Ophthalmol Vis Sci. 2011 Aug 5;52(9):6206-12. Print 2011 Aug., [PMID:21330655]

Abstract [show]
PURPOSE: Mutations in ABCA4 have been associated with autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa. The purpose of this study was to determine (1) associations among mutations and polymorphisms and (2) the role of the polymorphisms as protector/risk factors. METHODS: A case-control study was designed in which 128 Spanish patients and 84 control individuals were analyzed. Patient samples presented one or two mutated alleles previously identified using ABCR400 microarray and sequencing. RESULTS: A total of 18 previously described polymorphisms were studied in patients and control individuals. All except one presented a polymorphisms frequency higher than 5% in patients, and five mutations were found to have a frequency >5%. The use of statistical methods showed that the frequency of the majority of polymorphisms was similar in patients and controls, except for the IVS10+5delG, p.Asn1868Ile, IVS48+21C>T, and p.Arg943Gln polymorphisms. In addition, IVS48+21C>T and p.Arg943Gln were found to be in linkage disequilibrium with the p.Gly1961Glu and p.Arg602Trp mutations, respectively. CONCLUSIONS: Although the high allelic heterogeneity in ABCA4 and the wide spectrum of many common and rare polymorphisms complicate the interpretation of clinical relevance, polymorphisms were identified that may act as risk factors (p.Asn1868Ile) and others that may act as protection factors (p.His423Arg and IVS10+5 delG).

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9 The use of statistical methods showed that the frequency of the majority of polymorphisms was similar in patients and controls, except for the IVS10ϩ5delG, p.Asn1868Ile, IVS48ϩ21CϾT, and p.Arg943Gln polymorphisms. Login to comment
10 In addition, IVS48ϩ21CϾT and p.Arg943Gln were found to be in linkage disequilibrium with the p.Gly1961Glu and p.Arg602Trp mutations, respectively. Login to comment
85 Most Frequent ABCA4 Polymorphisms Found in Patients and Controls Exon Nucleotide Change Amino Acid Change Patients n (%) Allele Frequency n (%) Controls n (%) Allele Frequency n (%) P - IVS48؉21C>T SPLICE 13 (10.2) 13 (5.1) 0 (0.0) 0 (0.0) 0.003 - IVS10؉5 delG SPLICE 36 (28.1) 40 (15.6) 39 (46.4) 43 (25.6) 0.006 40 c.5603A>T p.Asn1868Ile 27 (21.1) 30 (11.7) 9 (10,7) 9 (5.3) 0.049 19 c.2828GϾA p.Arg943Gln 13 (10.2) 15 (5.8) 3 (3.6) 3 (1.8) 0.076 45 c.6249CϾT p.Ile2083Ile 14 (10.9) 15 (5.8) 16 (19.0) 18 (10.7) 0.098 49 c.6764GϾT p.Ser2255Ile 13 (10.2) 13 (5.1) 15 (17.9) 16 (9.5) 0.105 10 c.1268AϾG p.His423Arg 68 (53.1) 84 (32.8) 54 (64.3) 60 (35.7) 0.108 40 c.5682GϾC p.Leu1894Leu 70 (54.7) 90 (35.1) 37 (44.0) 41 (24.4) 0.130 42 c.5843CAϾTG p.Pro1948Leu 13 (10.2) 13 (5.1) 14 (16.7) 15 (8.9) 0.164 8 c.981CϾT p.Pro327Pro 2 (1.6) 2 (0.8) 0 (0.0) 0 (0.0) 0.250 6 c.635GϾA p.Arg212His 8 (6.3) 11 (4.3) 8 (9.5) 8 (4.7) 0.377 41 c.5814AϾG p.Leu1938Leu 40 (31.3) 48 (18.7) 31 (36.9) 35 (20.8) 0.394 44 c.6069CϾT p.Ile2023Ile 17 (13.3) 17 (6.6) 14 (16.7) 15 (8.9) 0.495 IVS33ϩ48CϾT SPLICE 109 (85.2) 170 (66.4) 74 (88.1) 93 (55.3) 0.542 28 c.4203CϾA/T p.Pro1401Pro 10 (7.8) 10 (3.9) 5 (6.0) 5 (2.9) 0.605 10 c.1269CϾT p.His423His 8 (6.3) 8 (3.1) 4 (4.8) 4 (2.4) 0.647 42 c.5844AϾG p.Pro1948Pro 36 (28.1) 42 (16.4) 23 (27.4) 25 (14.9) 0.906 46 c.6285TϾC p.Asp2095Asp 39 (30.5) 43 (16.8) 25 (29.8) 27 (16.1) 0.913 Variants revealing significant differences between both groups are shown in bold. Login to comment
86 the patient group: p.Asn1868Ile (P ϭ 0.013) and p.His423Arg (P ϭ 0 0.023) (Table 3). Login to comment
89 Using the Pearson`s ␹2 test, a significant association was detected between this alteration and the p.Arg943Gln polymorphism (P Ͻ 0.001), since 62.5% of the patients showed both sequence variants. Login to comment
90 Moreover, p.Arg943Gln was found in higher proportion in patients than in control individuals (P ϭ 0.076) (Table 2; Fig. 1). Login to comment
91 In contrast with this, the p.Leu1938Leu variant was less frequently detected among patients with p.Arg602Trp and had a frequency of 0% (P ϭ 0.05) (Table 3). Login to comment
109 Association between the Most Frequent ABCA4 Polymorphisms and Mutations Patients Variants Frequency P Status Predicted Effect Mutation, n (%) p.Arg1129Leu 34 (26.6) Present polymorphisms p.His423Arg 94.1% 0.000 Associated Risk IVS33؉48C>T 100% 0.011 Associated Risk IVS10ϩ5delG 20.6% 0.049 Associated Protector p.Leu1938Leu 17.6% 0.033 Associated Protector p.Ser2255Ile 2.9% 0.054 Associated Protector Mutation, n (%) p.Gly1961Glu 18 (14.1) Present polymorphisms p.Pro1948Pro 94.7% 0.000 Associated Risk p.Leu1938Leu 89.5% 0.000 Associated Risk p.Asp2095Asp 78.9% 0.000 Associated Risk IVS48؉21C>T 70.0% 0.000 Associated Risk IVS10؉5delG 57.9% 0.008 Associated Risk p.His423Arg 31.6% 0.016 Associated Protector p.Asn1868Ile 18.7% 0.039 Associated Protector Mutation, n (%) p.Arg602Trp 8 (6.3%) Present polymorphisms p.Arg943Gln 62.5% 0.000 Associated Risk p.Pro1401Pro 25% 0.044 Associated Protector p.Leu1938Leu 0% 0.041 Associated Protector Mutation, n (%) c.3211insGT 7 (5.5%) Present polymorphisms p.His423Arg 100% 0.021 Associated Risk p.Asn1868Ile 100% 0.000 Associated Risk IVS10ϩ5delG 0% 0.047 Associated Protector Mutation, n (%) p.Leu2060Arg 7 (5.5%) Present polymorphisms p.Leu1938Leu 100% 0.000 Associated Risk p.Pro1948Leu 100% 0.000 Associated Risk p.His423Arg 14.3% 0.019 Associated Protector TABLE 4. Login to comment
129 The p.Arg943Gln polymorphism is in linkage disequilibrium with the p.Arg602Trp mutation in Spanish STGD (P Ͻ 0.001, Table 3). Login to comment
130 However, in other European studies the p.Arg943Gln variant was detected in linkage disequilibrium with the p.Gly863Ala mutation,18,19,20 and 21 but this mutation has a low frequency in our series of patients, and no association analysis was performed. Login to comment
131 This change has been described showing diminished activity of the ABCA4 protein.11,22 However, using a SIFT and a Polyphen prediction, the p.Arg943Gln variant would not affect the protein function, so it is not clear how it affects the phenotype. Login to comment
136 We found an association between p.Arg602Trp and p.Arg943Gln that has not been observed in other populations. Login to comment
149 The p.Arg943Gln polymorphism is in linkage disequilibrium with the p.Arg602Trp mutation in Spanish STGD (P b0d; 0.001, Table 3). Login to comment
150 However, in other European studies the p.Arg943Gln variant was detected in linkage disequilibrium with the p.Gly863Ala mutation,18,19,20 and 21 but this mutation has a low frequency in our series of patients, and no association analysis was performed. Login to comment
151 This change has been described showing diminished activity of the ABCA4 protein.11,22 However, using a SIFT and a Polyphen prediction, the p.Arg943Gln variant would not affect the protein function, so it is not clear how it affects the phenotype. Login to comment
156 We found an association between p.Arg602Trp and p.Arg943Gln that has not been observed in other populations. Login to comment

[hide] Analysis of autofluorescent retinal images and mea... Exp Eye Res. 2010 Aug;91(2):143-52. Epub 2010 Apr 14. Chen B, Tosha C, Gorin MB, Nusinowitz S
Analysis of autofluorescent retinal images and measurement of atrophic lesion growth in Stargardt disease.
Exp Eye Res. 2010 Aug;91(2):143-52. Epub 2010 Apr 14., [PMID:20398653]

Abstract [show]
Current retinal imaging techniques using scanning laser ophthalmoscopy (SLO) provide a powerful mechanism for characterizing the topographical distribution of lipofuscin fluorophores and atrophic lesions (ALs) in retinal disease. In this paper we describe a novel Edge-Flow-Driven Variational Image Segmentation analysis to measure and evaluate progressive change in the area of ALs as well as regions of hyperfluorescence (HF). The algorithm is embedded in a series of almost completely automated image processing steps that allow rapid comparison of serial images. The sensitivity of the methodology to detect change was evaluated by measuring progression of AF lesion size in a cohort of Stargardt Macular Dystrophy (STGD) patients. Fifty-two STGD subjects (mean age = 41.0 +/- 16.6 years, range 9-78 yrs) at varying stages of disease participated in this prospective study. Twenty-four of the 52 subjects presented with atrophic lesions in one or both eyes on first evaluation. For this subgroup of subjects, the mean (+/-1 sd) follow-up time was 2.92 (+0.26) years (range 0.57-3.26 years) and the mean (+/-1 sd) rate of change was found to be approximately 0.94 (+/-0.87) mm(2)/year (range 0.2-2.13 mm(2)/yr). With this methodology, progressive enlargement of AL area was detectable in as little as one year, while regions of HF generally decreased, although there was considerable variability in the appearnce of HF, presumably reflecting the combined effects of the creation or expansion of lipofuscin deposits and resorption and loss associated with retinal cell death. Our findings suggest that this methodology is sufficiently sensitive to detect change and provides a clinically relevant tool to monitor progression not only with regards to natural history, but also to evaluate the efficacy of potential therapeutic interventions in STGD. Finally, we evaluated the association between AL area and measures of rod- and cone-mediated retinal function, as assessed with electroretinography (ERG). In general, the larger the AL, the poorer the ERG response, with a greater impact of lesion size on cone- rather than rod-mediated retinal function, a finding that was expected on the basis of the location and size of the AL and the distribution of rod- and cone-photoreceptors.

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No. Sentence Comment
82 ID# Age Years followed Visual Acuity AL Area (mm2 ) HF Area (mm2 ) ffERG Amplitudes (mV) ffERG IT (msec) ABCA4 Variants OD OS OD OS OD OS OD OS OD OS Rod Cone Rod Cone Rod Cone Rod Cone AI AII Group A S0047 53 2.83 20/40 20/40 31.60 33.85 0.20 0.07 304.0 125.4 392.9 143.3 69.5 29.3 72.7 29.3 NF NF S0023 49 3.26 20/160 20/160 9.92 12.67 1.24 1.49 292.1 52.2 272.4 46.4 77.9 36.8 78.3 35.2 L541P/A1038V NF S0050 78 2.71 20/250 20/160 2.02 0.07 1.21 0.67 355.0 82.2 373.1 87.2 76.7 34.1 76.7 34.8 S2255I IVS5,þ1,G > C S0045 44 3.16 20/200 20/160 17.27 44.72 NM NM 177.0 55.7 201.9 50.0 85.3 41.5 87.7 39.9 L541P/A1038V R2107K S0018 35 2.28 20/200 20/250 4.31 2.53 NM NM ND ND ND ND ND ND ND ND G1961E S2255I S0033 63 2.35 20/800 20/400 15.51 12.09 1.30 0.22 168.2 53.0 180.9 45.4 96.3 38.0 101.0 38.4 R943Q IVS8,-9, T > C S0048 62 2.56 20/80 20/20 48.45 40.73 NM NM 119.7 69.5 213.9 54.6 71.2 35.6 80.6 35.2 R290Q K346T S0036 62 2.81 20/640 20/500 55.70 43.38 NM NM 174.8 41.1 158.1 50.8 106.6 38.5 102.3 35.2 R1129L Q234X S0029 62 2.81 20/40 20/80 57.62 61.25 NM NM 219.0 26.0 209.2 35.2 77.9 31.3 73.6 30.9 R2030Q NF S0024 43 3.20 20/25 20/25 4.91 3.91 4.18 1.48 98.2 23.7 148.0 36.2 84.0 33.2 85.5 33.6 NF NF S0078 35 1.17 20/100 20/125 5.64 5.39 0.70 0.83 230.1 106.7 187.6 108.8 71.2 34.1 64.6 34.1 IVS39-10,T > C NF S0032 64 2.56 20/250 20/320 8.67 3.67 0.67 0.74 273.2 75.5 235.1 114.7 87.9 30.5 72.7 30.1 R1108C L2027F S0051 52 1.90 20/25 20/20 32.78 29.23 NM NM ND ND ND ND ND ND ND ND E471K NF S0115 16 0.57 20/50 20/50 0.77 3.43 NM NM ND ND ND ND ND ND ND ND NF NF S0077 49 1.14 20/40 20/25 N/A 8.54 0.16 1.89 279.9 111.9 299.3 105.2 N/A N/A N/A N/A NF NF S0042 43 1.84 20/125 20/200 118.15 126.69 NM NM 122.3 27.7 114.8 29.3 85.7 36.4 89.6 36.0 S2255I E471K S0037 46 2.38 20/125 20/200 8.73 N/A 1.29 0.86 338.7 119.3 373.7 109.4 72.3 28.1 70.7 28.1 G1961E S2255I S0020 42 0.0 20/200 20/160 1.16 1.82 NM NM 140.4 43.2 159.9 45.8 81.3 31.3 71.5 29.3 NF NF S0041 44 0.0 20/200 20/160 4.73 7.09 0.96 1.36 260.5 65* 297.2 95.3 113.7 29.7 91.8 28.9 R1129L NF S0087 44 0.0 20/20 20/20 14.89 23.09 NM NM 180.9 66.8 182.2 78.0 76.1 32.9 72.2 32.9 IVS40, þ5,G > A NF S0053 43 0.0 20/100 20/160 1.33 1.85 NM NM ND ND ND ND ND ND ND ND S2255I NF S0097 73 0.0 20/200 20/200 49.21 54.26 NM NM ND ND ND ND ND ND ND ND D1532E NF S0080 28 0.0 20/125 20/200 NA 0.98 0.56 0.03 333.1 117.2 325.1 121.4 80.2 32.5 82.6 32.9 E1122K S2255I S0210 49 0.0 20/160 20/200 0.21 NA NM NM 304.1 76.1 425.7 81.1 72.8 33.7 79.8 33.7 NF NF Group B S0133 30 0.0 20/125 20/32 0.51 0.01 387.1 123.7 374.8 105.1 65.4 32.9 65.0 32.9 NF NF S0046 49 0.0 20/160 20/160 1.48 1.68 491.2 148.9 494.9 145.3 72.7 30.1 77.3 29.7 P1380L G1961E S0141 40 0.0 20/13 20/32 1.88 0.41 389.0 156.5 343.5 150.6 70.8 33.3 69.7 34.4 NF NF S0058 61 0.0 20/50 20/50 1.48 1.52 ND ND ND ND ND ND ND ND NF NF S0149 16 0.0 20/80 20/100 1.59 0.62 285.0 87.4 333.4 115.3 62.6 32.5 61.4 32.5 NF NF S0083 15 0.0 20/13 20/13 0.17 0.48 441.1 144.2 472.0 155.5 74.4 33.3 71.6 33.3 G863A NF S0216 44 0.0 20/25 20/32 0.52 1.04 228.7 97.7 192.7 75.3 83.8 36.8 85.7 36.0 NF NF S0076 9 0.0 20/200 20/160 3.70 4.23 557.7 139.5 319.8 117.3 81.6 29.7 73.4 28.9 W1408R T1526M S0021 19 0.0 20/160 20/160 1.81 1.08 390.4 202.1 ND ND 63.3 29.3 ND ND L2027F W31R S0085 35 0.0 20/16 20/20 2.70 2.56 ND ND ND ND ND ND ND ND C54T R219T S0044 30 0.0 20/250 20/250 4.23 3.77 ND ND ND ND ND ND ND ND A1794D L2027F S0035 47 0.0 20/160 20/125 0.46 0.13 239.6 112.3 325.0 141.6 64.1 28.1 62.5 28.1 G863A E471K S0065 61 0.0 20/100 20/125 0.83 0.15 243.4 58.6 226.5 49.2 74.8 32.9 84.5 33.3 G1961E NF S0213 27 0.0 20/25 20/25 0.99 1.03 384.2 124.4 424.4 137.9 72.4 31.7 72.4 35.2 NF NF S0088 55 0.0 20/25 20/20 0.11 0.47 ND ND ND ND ND ND ND ND R1898H NF S0127 16 0.0 20/63 20/63 0.08 0.69 536.3 128.9 470.3 136.4 65.4 30.9 77.1 30.9 L541P/A1038V NF S0057 47 0.48 20/125 20/160 1.20 1.75 252.1 80.3 210.5 100.5 75.5 32.9 89.6 32.5 NF NF S0043 53 2.91 20/200 20/200 0.97 0.53 250.5 173.2 354.6 179.2 72.7 28.5 80.1 30.1 G1961E F873I S0101 37 1.1 20/40 20/20 0.14 0.25 382.2 159.7 422.7 156.7 70.5 32.5 74.0 32.9 A1038V IVS42 þ 1,G > A S0027 17 2.18 20/50 20/50 1.60 2.12 196.3 36.3 198.0 51.0 84.7 32.9 98.8 35.3 NF NF S0104 20 1.19 20/160 20/200 0.05 0.12 237.4 77.7 440.1 88.7 63.0 30.9 64.6 30.1 NF NF S0110 26 1.02 20/200 20/125 0.65 0.56 333.8 94.5 349.4 98.7 68.9 32.1 68.9 32.5 R1129L NF S0049 34 2.13 20/50 20/200 0.76 0.92 374.4 97.2 344.0 90.5 81.0 32.9 65.8 33.7 R1129L NF S0075 22 1.06 20/63 20/125 0.40 0.69 454.5 114.0 452.7 122.8 77.5 32.1 75.5 32.9 G1961E NF S0039 36 2.2 20/160 20/100 0.15 0.13 347.7 137.1 395.8 142.0 80.1 31.3 61.7 30.9 M1V R2107H S0054 31 1.93 20/40 20/40 0.41 0.56 ND ND ND ND ND ND ND ND G1961E S2255I S0040 11 2.97 20/160 20/160 0.46 0.07 610.2 72.5 375.6 67.4 106.5 37.2 93.5 32.9 R572X N1805D S0028 54 2.73 20/16 20/16 1.04 1.54 425.5 105.8 386.3 107.8 83.4 34.4 84.1 34.8 L541P/A1038V R2030Q ND ¼ not done. Login to comment
81 ID# Age Years followed Visual Acuity AL Area (mm2 ) HF Area (mm2 ) ffERG Amplitudes (mV) ffERG IT (msec) ABCA4 Variants OD OS OD OS OD OS OD OS OD OS Rod Cone Rod Cone Rod Cone Rod Cone AI AII Group A S0047 53 2.83 20/40 20/40 31.60 33.85 0.20 0.07 304.0 125.4 392.9 143.3 69.5 29.3 72.7 29.3 NF NF S0023 49 3.26 20/160 20/160 9.92 12.67 1.24 1.49 292.1 52.2 272.4 46.4 77.9 36.8 78.3 35.2 L541P/A1038V NF S0050 78 2.71 20/250 20/160 2.02 0.07 1.21 0.67 355.0 82.2 373.1 87.2 76.7 34.1 76.7 34.8 S2255I IVS5,&#fe;1,G > C S0045 44 3.16 20/200 20/160 17.27 44.72 NM NM 177.0 55.7 201.9 50.0 85.3 41.5 87.7 39.9 L541P/A1038V R2107K S0018 35 2.28 20/200 20/250 4.31 2.53 NM NM ND ND ND ND ND ND ND ND G1961E S2255I S0033 63 2.35 20/800 20/400 15.51 12.09 1.30 0.22 168.2 53.0 180.9 45.4 96.3 38.0 101.0 38.4 R943Q IVS8,-9, T > C S0048 62 2.56 20/80 20/20 48.45 40.73 NM NM 119.7 69.5 213.9 54.6 71.2 35.6 80.6 35.2 R290Q K346T S0036 62 2.81 20/640 20/500 55.70 43.38 NM NM 174.8 41.1 158.1 50.8 106.6 38.5 102.3 35.2 R1129L Q234X S0029 62 2.81 20/40 20/80 57.62 61.25 NM NM 219.0 26.0 209.2 35.2 77.9 31.3 73.6 30.9 R2030Q NF S0024 43 3.20 20/25 20/25 4.91 3.91 4.18 1.48 98.2 23.7 148.0 36.2 84.0 33.2 85.5 33.6 NF NF S0078 35 1.17 20/100 20/125 5.64 5.39 0.70 0.83 230.1 106.7 187.6 108.8 71.2 34.1 64.6 34.1 IVS39-10,T > C NF S0032 64 2.56 20/250 20/320 8.67 3.67 0.67 0.74 273.2 75.5 235.1 114.7 87.9 30.5 72.7 30.1 R1108C L2027F S0051 52 1.90 20/25 20/20 32.78 29.23 NM NM ND ND ND ND ND ND ND ND E471K NF S0115 16 0.57 20/50 20/50 0.77 3.43 NM NM ND ND ND ND ND ND ND ND NF NF S0077 49 1.14 20/40 20/25 N/A 8.54 0.16 1.89 279.9 111.9 299.3 105.2 N/A N/A N/A N/A NF NF S0042 43 1.84 20/125 20/200 118.15 126.69 NM NM 122.3 27.7 114.8 29.3 85.7 36.4 89.6 36.0 S2255I E471K S0037 46 2.38 20/125 20/200 8.73 N/A 1.29 0.86 338.7 119.3 373.7 109.4 72.3 28.1 70.7 28.1 G1961E S2255I S0020 42 0.0 20/200 20/160 1.16 1.82 NM NM 140.4 43.2 159.9 45.8 81.3 31.3 71.5 29.3 NF NF S0041 44 0.0 20/200 20/160 4.73 7.09 0.96 1.36 260.5 65* 297.2 95.3 113.7 29.7 91.8 28.9 R1129L NF S0087 44 0.0 20/20 20/20 14.89 23.09 NM NM 180.9 66.8 182.2 78.0 76.1 32.9 72.2 32.9 IVS40, &#fe;5,G > A NF S0053 43 0.0 20/100 20/160 1.33 1.85 NM NM ND ND ND ND ND ND ND ND S2255I NF S0097 73 0.0 20/200 20/200 49.21 54.26 NM NM ND ND ND ND ND ND ND ND D1532E NF S0080 28 0.0 20/125 20/200 NA 0.98 0.56 0.03 333.1 117.2 325.1 121.4 80.2 32.5 82.6 32.9 E1122K S2255I S0210 49 0.0 20/160 20/200 0.21 NA NM NM 304.1 76.1 425.7 81.1 72.8 33.7 79.8 33.7 NF NF Group B S0133 30 0.0 20/125 20/32 0.51 0.01 387.1 123.7 374.8 105.1 65.4 32.9 65.0 32.9 NF NF S0046 49 0.0 20/160 20/160 1.48 1.68 491.2 148.9 494.9 145.3 72.7 30.1 77.3 29.7 P1380L G1961E S0141 40 0.0 20/13 20/32 1.88 0.41 389.0 156.5 343.5 150.6 70.8 33.3 69.7 34.4 NF NF S0058 61 0.0 20/50 20/50 1.48 1.52 ND ND ND ND ND ND ND ND NF NF S0149 16 0.0 20/80 20/100 1.59 0.62 285.0 87.4 333.4 115.3 62.6 32.5 61.4 32.5 NF NF S0083 15 0.0 20/13 20/13 0.17 0.48 441.1 144.2 472.0 155.5 74.4 33.3 71.6 33.3 G863A NF S0216 44 0.0 20/25 20/32 0.52 1.04 228.7 97.7 192.7 75.3 83.8 36.8 85.7 36.0 NF NF S0076 9 0.0 20/200 20/160 3.70 4.23 557.7 139.5 319.8 117.3 81.6 29.7 73.4 28.9 W1408R T1526M S0021 19 0.0 20/160 20/160 1.81 1.08 390.4 202.1 ND ND 63.3 29.3 ND ND L2027F W31R S0085 35 0.0 20/16 20/20 2.70 2.56 ND ND ND ND ND ND ND ND C54T R219T S0044 30 0.0 20/250 20/250 4.23 3.77 ND ND ND ND ND ND ND ND A1794D L2027F S0035 47 0.0 20/160 20/125 0.46 0.13 239.6 112.3 325.0 141.6 64.1 28.1 62.5 28.1 G863A E471K S0065 61 0.0 20/100 20/125 0.83 0.15 243.4 58.6 226.5 49.2 74.8 32.9 84.5 33.3 G1961E NF S0213 27 0.0 20/25 20/25 0.99 1.03 384.2 124.4 424.4 137.9 72.4 31.7 72.4 35.2 NF NF S0088 55 0.0 20/25 20/20 0.11 0.47 ND ND ND ND ND ND ND ND R1898H NF S0127 16 0.0 20/63 20/63 0.08 0.69 536.3 128.9 470.3 136.4 65.4 30.9 77.1 30.9 L541P/A1038V NF S0057 47 0.48 20/125 20/160 1.20 1.75 252.1 80.3 210.5 100.5 75.5 32.9 89.6 32.5 NF NF S0043 53 2.91 20/200 20/200 0.97 0.53 250.5 173.2 354.6 179.2 72.7 28.5 80.1 30.1 G1961E F873I S0101 37 1.1 20/40 20/20 0.14 0.25 382.2 159.7 422.7 156.7 70.5 32.5 74.0 32.9 A1038V IVS42 &#fe; 1,G > A S0027 17 2.18 20/50 20/50 1.60 2.12 196.3 36.3 198.0 51.0 84.7 32.9 98.8 35.3 NF NF S0104 20 1.19 20/160 20/200 0.05 0.12 237.4 77.7 440.1 88.7 63.0 30.9 64.6 30.1 NF NF S0110 26 1.02 20/200 20/125 0.65 0.56 333.8 94.5 349.4 98.7 68.9 32.1 68.9 32.5 R1129L NF S0049 34 2.13 20/50 20/200 0.76 0.92 374.4 97.2 344.0 90.5 81.0 32.9 65.8 33.7 R1129L NF S0075 22 1.06 20/63 20/125 0.40 0.69 454.5 114.0 452.7 122.8 77.5 32.1 75.5 32.9 G1961E NF S0039 36 2.2 20/160 20/100 0.15 0.13 347.7 137.1 395.8 142.0 80.1 31.3 61.7 30.9 M1V R2107H S0054 31 1.93 20/40 20/40 0.41 0.56 ND ND ND ND ND ND ND ND G1961E S2255I S0040 11 2.97 20/160 20/160 0.46 0.07 610.2 72.5 375.6 67.4 106.5 37.2 93.5 32.9 R572X N1805D S0028 54 2.73 20/16 20/16 1.04 1.54 425.5 105.8 386.3 107.8 83.4 34.4 84.1 34.8 L541P/A1038V R2030Q ND &#bc; not done. Login to comment

[hide] Novel mutations in of the ABCR gene in Italian pat... Eye (Lond). 2010 Jan;24(1):158-64. Epub 2009 Mar 6. Passerini I, Sodi A, Giambene B, Mariottini A, Menchini U, Torricelli F
Novel mutations in of the ABCR gene in Italian patients with Stargardt disease.
Eye (Lond). 2010 Jan;24(1):158-64. Epub 2009 Mar 6., [PMID:19265867]

Abstract [show]
PURPOSE: Stargardt disease (STGD) is the most prevalent juvenile macular dystrophy, and it has been associated with mutations in the ABCR gene, encoding a photoreceptor-specific transport protein. In this study, we determined the mutation spectrum in the ABCR gene in a group of Italian STGD patients. METHODS: The DNA samples of 71 Italian patients (from 62 independent pedigrees), affected with autosomal recessive STGD, were analysed for mutations in all 50 exons of the ABCR gene by the DHPLC approach (with optimization of the DHPLC conditions for mutation analysis) and direct sequencing techniques. RESULTS: In our group of STGD patients, 71 mutations were identified in 68 patients with a detection rate of 95.7%. Forty-three mutations had been already reported in the literature, whereas 28 mutations had not been previously described and were not detected in 150 unaffected control individuals of Italian origin. Missense mutations represented the most frequent finding (59.2%); G1961E was the most common mutation and it was associated with phenotypes in various degrees of severity. CONCLUSIONS: Some novel mutations in the ABCR gene were reported in a group of Italian STGD patients confirming the extensive allelic heterogeneity of this gene-probably related to the vast number of exons that favours rearrangements in the DNA sequence.

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83 In our series, mainly consisting of patients coming from central Italy, G1961E was the most common mutant allele, in congruence with other studies performed in distinct dissimilar European populations.9,20 Nevertheless, the frequency of G1961E mutation (20.4% of our STGD alleles) was higher than in the other Italian Table 3 Summary of the polymorphic variants identified in the ABCR gene in our series of STGD Italian patients Location Polymorphic variants Number of alleles Exon 3 IVS3 þ 26a4g 14 Exon 5 D159 1 Exon 6 R212H 6 Exon 7 IVS7-32t4c 9 Exon 10 H423R 12 Exon 13 D644 1 Exon 14 IVS14 þ 50t4c 1 Exon 15 IVS15-13t4c 2 Exon 16 IVS16-13c4t 1 Exon 19 R943Q 3 Exon 20 L1988 1 Exon 23 Q1169 4 Exon 23 IVS23 þ 25g4a 2 Exon 24 T1176 6 Exon 24 K1182 3 Exon 28 P1401 1 Exon 33 IVS33-39t4c 2 Exon 34 IVS34 þ 16insgtt 4 Exon 38 D1817Q 7 Exon 40 N1868I 3 Exon 40 L1894 16 Exon 41 L1938 15 Exon 42 P1948 23 Exon 44 I2023 5 Exon 44 IVS44-16g4a 5 Exon 44 IVS44 þ 77g4a 1 Exon 45 I2083 5 Exon 46 D2095 19 Exon 48 IVS48 þ 21c4t 3 Exon 49 S2255I 5 studies where this mutation was detected in 11.110 and 9.7% 11 of the screened alleles. 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] ABCA4 mutations in Portuguese Stargardt patients: ... Mol Vis. 2009;15:584-91. Epub 2009 Mar 25. Maia-Lopes S, Aguirre-Lamban J, Castelo-Branco M, Riveiro-Alvarez R, Ayuso C, Silva ED
ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis.
Mol Vis. 2009;15:584-91. Epub 2009 Mar 25., [PMID:19365591]

Abstract [show]
PURPOSE: To resolve the spectrum of causative retina-specific ATP-binding cassette transporter gene (ABCA4) gene mutations in Portuguese Stargardt (STGD) patients and compare allele frequencies obtained in this cohort with those of previous population surveys. METHODS: Using a microarray technique (ABCR400 gene chip), we screened all previously reported ABCA4 gene mutations in the genomic DNA of 27 patients from 21 unrelated Stargardt families whose phenotypes had been clinically evaluated using psychophysics and electrophysiological measurements. Furthermore, we performed denaturing high performance liquid chromatography whenever one or both mutant alleles failed to be detected using the ABCR gene chip. RESULTS: A total of 36 mutant alleles (out of the 54 tested) were identified in STGD patients, resulting in a detection rate of 67%. Two mutant alleles were present in 12 out of 21 STGD families (57%), whereas in four out of 21 (19%) of the families, only one mutant allele was found. We report the presence of 22 putative pathogenic alterations, including two sequence changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease-associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X). The great majority of the mutations were missense (72.7%). Seven frameshift variants (19.4%), three nonsense mutations (8.3%), and one splicing sequence change (2.7%) were also found in STGD chromosomes. The most prevalent pathologic variant was the missense mutation p.Leu11Pro. Present in 19% of the families, this mutation represents a quite high prevalence in comparison to other European populations. In addition, 23 polymorphisms were also identified, including four novel intronic sequence variants. CONCLUSIONS: To our knowledge, this study represents the first report of ABCA4 mutations in Portuguese STGD patients and provides further evidence of different mutation frequency across populations. Phenotypic characterization of novel putative mutations was addressed.

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111 Exon Nucleotide Change Effect STGD Families Frequency References IVS3 c.302+20C>T - 12 4.8% [6] IVS3 c.302+26A>G - 7,12,13,14 1.91% [6] 6 c.635G>A p.Arg212His 13,19 9.5% [15] IVS7 c.859+8T>C - 17 4.8% Present study 10 c.1268A>G p.His423Arg 2,4,5,6,10,11,12,13,14,18,19 53% [13] 10 c.1269C>T p.His423His 16 4.8% [13] IVS10 c.1356+5delG SPLICE 1,7,11,15,20 23.8% [13] IVS14 c.2161+47T>C - 18 4.8% Present study 19 c.2828G>A p.Arg943Gln 3,10,18,19 19.1% [5] IVS19 c.2919+34C>T - 12 4.8% Present study 20 c.2964T>C p.Leu988Leu 12 4.8% [6] IVS22 c.3326-19G>A - 2 4.8% Present study IVS33 c.4773+48C>T Splice 1,2,3,5,6,8,9,10,12,13,14,16,17,18,19,20 76.2% [13] 40 c.5603A>T p.Asn1868Ile 4,10,17 14.3% [6] 40 c.5682G>C p.Leu1894Leu 1,2,4,5,8,10,12,13,17,18 47.6% [6] 41 c.5814A>G p.Leu1938Leu 1,2,5,8,10,12,13,18 3.81% [6] 42 c.5843CA>TG/c.5843C>T p.Pro1948Leu 11 4.8% [14] 42 c.5844A>G p.Pro1948Pro 1,2,5,8,10,12,13 33.3% [14] 44 c.6069C>T p.Ile2023Ile 9,12,14,19 19.1% [6] 45 c.6249C>T p.Ile2083Ile 9,12,14,19 19.1% [5] 46 c.6285T>C p.Asp2095Asp 1,2,8,9,10,12,14,19 38.1% [14] IVS48 c.6769+21C>T SPLICE 1,10 9.5% [6] 49 c.6764G>T p.Ser2255Ile 1,9,14,19 19.1% [5] Several polymorphisms in exons and introns (IVS) throughout the entire ABCA4 gene were found in our study population. Login to comment
110 Exon Nucleotide Change Effect STGD Families Frequency References IVS3 c.302+20C>T - 12 4.8% [6] IVS3 c.302+26A>G - 7,12,13,14 1.91% [6] 6 c.635G>A p.Arg212His 13,19 9.5% [15] IVS7 c.859+8T>C - 17 4.8% Present study 10 c.1268A>G p.His423Arg 2,4,5,6,10,11,12,13,14,18,19 53% [13] 10 c.1269C>T p.His423His 16 4.8% [13] IVS10 c.1356+5delG SPLICE 1,7,11,15,20 23.8% [13] IVS14 c.2161+47T>C - 18 4.8% Present study 19 c.2828G>A p.Arg943Gln 3,10,18,19 19.1% [5] IVS19 c.2919+34C>T - 12 4.8% Present study 20 c.2964T>C p.Leu988Leu 12 4.8% [6] IVS22 c.3326-19G>A - 2 4.8% Present study IVS33 c.4773+48C>T Splice 1,2,3,5,6,8,9,10,12,13,14,16,17,18,19,20 76.2% [13] 40 c.5603A>T p.Asn1868Ile 4,10,17 14.3% [6] 40 c.5682G>C p.Leu1894Leu 1,2,4,5,8,10,12,13,17,18 47.6% [6] 41 c.5814A>G p.Leu1938Leu 1,2,5,8,10,12,13,18 3.81% [6] 42 c.5843CA>TG/c.5843C>T p.Pro1948Leu 11 4.8% [14] 42 c.5844A>G p.Pro1948Pro 1,2,5,8,10,12,13 33.3% [14] 44 c.6069C>T p.Ile2023Ile 9,12,14,19 19.1% [6] 45 c.6249C>T p.Ile2083Ile 9,12,14,19 19.1% [5] 46 c.6285T>C p.Asp2095Asp 1,2,8,9,10,12,14,19 38.1% [14] IVS48 c.6769+21C>T SPLICE 1,10 9.5% [6] 49 c.6764G>T p.Ser2255Ile 1,9,14,19 19.1% [5] Several polymorphisms in exons and introns (IVS) throughout the entire ABCA4 gene were found in our study population. Login to comment

[hide] Macular pigment and lutein supplementation in ABCA... Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1319-29. Aleman TS, Cideciyan AV, Windsor EA, Schwartz SB, Swider M, Chico JD, Sumaroka A, Pantelyat AY, Duncan KG, Gardner LM, Emmons JM, Steinberg JD, Stone EM, Jacobson SG
Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations.
Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1319-29., [PMID:17325179]

Abstract [show]
PURPOSE: To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS: Patients with Stargardt disease or cone-rod dystrophy and known or suspected disease-causing mutations in the ABCA4 gene were included. All patients had foveal fixation. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity, and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS: MPOD in patients ranged from normal to markedly abnormal. As a group, patients with ABCA4-RD had reduced foveal MPOD, and there was a strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients, whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein, and 63% of the patients' eyes showed a significant augmentation in MPOD. The retinal responders tended to be female and to have lower serum lutein and zeaxanthin, lower MPOD, and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration than did nonresponding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS: MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences of this supplement on the natural history of these macular degenerations require further study.

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61 Clinical and Molecular Characteristics of the Patients Patient Age (y)/Gender ABCA4 Mutation Visual Acuity* Refraction† Kinetic Visual Field Extent (V-4e)‡ Lutein Trial Participant?RE LE RE LE RE LE 1 18/M G863A/R943Q 20/32 20/32 -0.50 -0.50 109 105 Y 2 18/F E1087K/G1961E 20/25 20/25 -1.00 -1.25 103 104 N 3 18/M ࿣ 20/20 20/125 -1.00 -1.00 126 105 N 4§ 19/F R1129L/L1940P 20/40 20/50 ϩ0.25 ϩ0.25 90 93 Y 5 21/M P1511del1ccgC/R1705Q 20/25 20/25 -0.75 -0.25 103 107 Y 6 24/M T1019M/G1961E 20/50 20/200 -1.25 -1.50 112 105 Y 7§ 26/M ࿣ 20/40 20/32 ϩ1.00 ϩ0.75 86 88 Y 8 30/F ࿣ 20/50 20/40 ϩ2.25 ϩ1.75 105 110 Y 9 30/M R1108C/R152Q 20/20 20/32 -2.25 -3.50 99 93 Y 10 32/F V935A/IVS40ϩ5G3A 20/32 20/40 -0.75 -1.25 103 92 N 11 34/F R681X/R1300Q 20/20 20/20 -1.50 -1.75 110 96 N 12 37/M C54Y/G1961E 20/32 20/25 -3.00 -2.00 99 105 Y 13¶ 38/F V256V/G1961E 20/25 20/25 -1.00 -1.25 106 101 Y 14¶ 42/F V256V/G1961E 20/25 20/32 -0.50 -0.75 107 94 Y 15 47/F R1300Q/R2107H 20/32 20/20 ϩ0.75 ϩ0.25 108 103 N 16§ 49/M ࿣ 20/32 20/32 -4.50 -4.50 84 79 Y 17 56/M G1977S 20/25 20/25 -5.50 -5.50 99 109 N * Best corrected visual acuity. Login to comment
62 RE LE RE LE RE LE 1 18/M G863A/R943Q 20/32 20/32 afa;0.50 afa;0.50 109 105 Y 2 18/F E1087K/G1961E 20/25 20/25 afa;1.00 afa;1.25 103 104 N 3 18/M $f3; 20/20 20/125 afa;1.00 afa;1.00 126 105 N 4&#a7; 19/F R1129L/L1940P 20/40 20/50 af9;0.25 af9;0.25 90 93 Y 5 21/M P1511del1ccgC/R1705Q 20/25 20/25 afa;0.75 afa;0.25 103 107 Y 6 24/M T1019M/G1961E 20/50 20/200 afa;1.25 afa;1.50 112 105 Y 7&#a7; 26/M $f3; 20/40 20/32 af9;1.00 af9;0.75 86 88 Y 8 30/F $f3; 20/50 20/40 af9;2.25 af9;1.75 105 110 Y 9 30/M R1108C/R152Q 20/20 20/32 afa;2.25 afa;3.50 99 93 Y 10 32/F V935A/IVS40af9;5G3A 20/32 20/40 afa;0.75 afa;1.25 103 92 N 11 34/F R681X/R1300Q 20/20 20/20 afa;1.50 afa;1.75 110 96 N 12 37/M C54Y/G1961E 20/32 20/25 afa;3.00 afa;2.00 99 105 Y 13&#b6; 38/F V256V/G1961E 20/25 20/25 afa;1.00 afa;1.25 106 101 Y 14&#b6; 42/F V256V/G1961E 20/25 20/32 afa;0.50 afa;0.75 107 94 Y 15 47/F R1300Q/R2107H 20/32 20/20 af9;0.75 af9;0.25 108 103 N 16&#a7; 49/M $f3; 20/32 20/32 afa;4.50 afa;4.50 84 79 Y 17 56/M G1977S 20/25 20/25 afa;5.50 afa;5.50 99 109 N * Best corrected visual acuity. Login to comment

[hide] Spectrum of the ABCA4 gene mutations implicated in... Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90. Valverde D, Riveiro-Alvarez R, Aguirre-Lamban J, Baiget M, Carballo M, Antinolo G, Millan JM, Garcia Sandoval B, Ayuso C
Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients.
Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90., [PMID:17325136]

Abstract [show]
PURPOSE: The purpose of this study is to describe the spectrum of mutations in the ABCA4 gene found in Spanish patients affected with several retinal dystrophies. METHODS: Sixty Spanish families with different retinal dystrophies were studied. Samples were analyzed for variants in all 50 exons of the ABCA4 gene by screening with the ABCR400 microarray, and results were confirmed by direct sequencing. Haplotype analyses were also performed. For those families with only one mutation detected by the microarray, denaturing (d)HPLC was performed to complete the mutational screening of the ABCA4 gene. RESULTS: The sequence analysis of the ABCA4 gene led to the identification of 33 (27.5%) potential disease-associated alleles among the 60 patients. These comprised 16 distinct sequence variants in 25 of the 60 subjects investigated. For autosomal recessive cone-rod dystrophy (arCRD), we found that 50% of the CRD families with the mutation had two recurrent changes (2888delG and R943Q). For retinitis pigmentosa (RP) and autosomal dominant macular dystrophy (adMD), one putative disease-associated allele was identified in 9 of the 27 and 3 of the 7 families, respectively. CONCLUSIONS: In the population studied, ABCA4 plays an important role in the pathogenesis of arCRD. However, mutations in this gene are less frequently identified in other retinal dystrophies, like RP or adMD, and therefore it is still not clear whether ABCA4 is involved as a modifying factor or the relationship is a fortuitous association.

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9 For autosomal recessive cone-rod dystrophy (arCRD), we found that 50% of the CRD families with the mutation had two recurrent changes (2888delG and R943Q). Login to comment
56 TABLE 1. Genetic Analyses of ABCA4 Mutations in Three Families with Autosomal Dominant Macular Dystrophy Family Allele 1 Allele 2 Haplotype AnalysisNucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change ADDM-59 [5582G3A; 6764G3T] [G1961E; S22551] Excluded ADDM-92 466A3G I156V Not done ADDM-105 2828G3A R943Q Not done No change has been detected as allele 2. Login to comment
57 TABLE 2. Genetic Analyses of ABCA4 Mutations in 13 arCRD Families Family Allele 1 Allele 2 Haplotype AnalysisNucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change ARDM-79 2888delG Frameshift 2888delG Frameshift Cosegregates ARDM-85 6764G3T S2255I (likely nonpathogenic) Not detected Not done* ARDM-86 2888delG Frameshift 2888delG Frameshift Cosegregates ARDM-99 4297G3A V1433I Not detected Not done* ARDM-126 [2828G3A; 5929G3A] [R943Q; G1977S] [2828G3A; 5929G3A] [R943Q; G1977S] Cosegregates ARDM-133 32T3C L11P 2888delG Frameshift Cosegregates ARDM-134 2828G3A R943Q Excluded ARDM-174 4918C3T R1640W c.6147؉2T3A Splice Cosegregates ARDM-176 2888delG Frameshift 6179T3G L2060R Cosegregates RP-267 5041del 15 pb Frameshift 5041del 15 pb Frameshift Cosegregates RP-577 1140T3A N380K Not detected Not done* SRP-964 2828G3A R943Q Not detected Not done* B210 2828G3A R943Q 2701A3G T901A Not done* The mutation detected by dHPLC is in bold. Login to comment
68 For family ADDM-92, a mutation in the heterozygous state, I156V, was detected. Login to comment
69 Besides, a mild allele [R943Q] was detected in family ADDM-105. Login to comment
87 TABLE 3. Genetic Analyses of ABCA4 Changes in Nine Families with Autosomal Recessive RP Family Allele 1 Allele 2 Nucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change SRP-716 6764G3T S2255I (likely nonpathogenic) c.858 ؉8T3G SRP-766 2300T3A V767D c.858 ؉8T3G SRP-775 466A3G I156V c.858 ؉8T3G SRP-818 6764G3T S2255I (likely nonpathogenic) SRP-834 c.5547ϩ5G3A Splice acceptor SRP-854 6764G3T S2255I B57 466A3G I156V B173 2828G3A R943Q G5466A L1821L B278 2701A3G T901A [G1961E; S2255I] did not support the pathologic role of this mutation in the family. Login to comment
93 In fact, it has already been demonstrated that the ABCA4 and STGD3 genes can interact with each other, increasing the severity of the macular phenotype.12 In family ADDM-105, the R943Q mutation was detected. Login to comment
97 Therefore, we speculate about two possibilities: First, the R943Q change could be paired with a severer mutation not found in our study; or second, R943Q could have a modulating effect on another gene implicated in adMD, not discovered yet. Login to comment
99 In the case of family ADDM-92, which had the I156V mutation, the clinical phenotype seemed to be severer than that in family ADDM105, which presented the mild allele R943Q. Login to comment
107 For the [G1977S; R943Q] complex allele found in homozygosis, expression analysis of the G1977S mutation has determined that it causes the inhibition of ATPase by retinal,24 whereas R943Q leads to a reduced nucleotidase activity and nucleotide-binding capacity.22 The affected patients had an age at onset between 9 and 10 years and described night blindness at approximately 18 years of age. Login to comment
112 The family ARDM 174 presented two mutations, one the missense mutation R1640W detected by the ABCA400 microarray and with an unknown effect in the ABCR function, and the TABLE 4. Login to comment
115 The last arCRD family studied also presented two missense mutations, namely T901A and R943Q, the latter described as reducing the ATPase activity in 40% and producing minimal defects in nucleotide binding,22 being categorized as a mild mutation. Login to comment
117 In all the cases, they were missense mutations (Table 1), although two of them (R943Q and S2255I) are still controversial: R943Q reduces the ATPase activity, and S2255I is supposed to have limited pathogenicity. Login to comment
55 TABLE 1. Genetic Analyses of ABCA4 Mutations in Three Families with Autosomal Dominant Macular Dystrophy Family Allele 1 Allele 2 Haplotype Analysis Nucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change ADDM-59 [5582G3A; 6764G3T] [G1961E; S22551] Excluded ADDM-92 466A3G I156V Not done ADDM-105 2828G3A R943Q Not done No change has been detected as allele 2. Login to comment
85 TABLE 3. Genetic Analyses of ABCA4 Changes in Nine Families with Autosomal Recessive RP Family Allele 1 Allele 2 Nucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change SRP-716 6764G3T S2255I (likely nonpathogenic) c.858 d19;8T3G SRP-766 2300T3A V767D c.858 d19;8T3G SRP-775 466A3G I156V c.858 d19;8T3G SRP-818 6764G3T S2255I (likely nonpathogenic) SRP-834 c.5547af9;5G3A Splice acceptor SRP-854 6764G3T S2255I B57 466A3G I156V B173 2828G3A R943Q G5466A L1821L B278 2701A3G T901A [G1961E; S2255I] did not support the pathologic role of this mutation in the family. Login to comment
91 In fact, it has already been demonstrated that the ABCA4 and STGD3 genes can interact with each other, increasing the severity of the macular phenotype.12 In family ADDM-105, the R943Q mutation was detected. Login to comment
95 Therefore, we speculate about two possibilities: First, the R943Q change could be paired with a severer mutation not found in our study; or second, R943Q could have a modulating effect on another gene implicated in adMD, not discovered yet. Login to comment
105 For the [G1977S; R943Q] complex allele found in homozygosis, expression analysis of the G1977S mutation has determined that it causes the inhibition of ATPase by retinal,24 whereas R943Q leads to a reduced nucleotidase activity and nucleotide-binding capacity.22 The affected patients had an age at onset between 9 and 10 years and described night blindness at approximately 18 years of age. Login to comment
114 In all the cases, they were missense mutations (Table 1), although two of them (R943Q and S2255I) are still controversial: R943Q reduces the ATPase activity, and S2255I is supposed to have limited pathogenicity. 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] 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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121 The first visual field in Table 3 Functional implications of missense and splice site mutations Mutation Type of mutation Predicted effect on ABCR function 768G→T Splice site No protein [34] G683A/ΔG863 Missense Decreased ATPase activity [54, 57] R943Q Missense Decreased ATPase activity [54] IVS38-10T→C Splice site Variant in linkage disequilibrium with unknown mutation [39] IVS40+5G→A Splice site Some residual ABCR function [39] G1961E Missense Decreased ATP binding and ATPase activity [57] Fig. 1 Fundus photographs of the patients in this study. Login to comment
122 The first visual field in Table 3 Functional implications of missense and splice site mutations Mutation Type of mutation Predicted effect on ABCR function 768G࢐T Splice site No protein [34] G683A/ƊG863 Missense Decreased ATPase activity [54, 57] R943Q Missense Decreased ATPase activity [54] IVS38-10T࢐C Splice site Variant in linkage disequilibrium with unknown mutation [39] IVS40+5G࢐A Splice site Some residual ABCR function [39] G1961E Missense Decreased ATP binding and ATPase activity [57] Fig. 1 Fundus photographs of the patients in this study. 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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61 15680 Isolated 5882G4A G1961E Not identified NA 15730 Isolated 2588G4C; 2828G4A DG863/G863A; R943Q 2588G4C; 2828G4A DG863/G863A; R943Q ? Login to comment
65 16697 Isolated 2588G4C; 2828G4Ab DG863/G863A; R943Q 1853G4A; 4297G4A G618E; V1433I Yes 16755 Isolated 2588G4C; 2828G4A DG863/G863A; R943Q Not identified NA 16887 Isolated 768G4T Splicing IVS38-10T4C Unknowna Yes 17906 Aut. rec. 768G4T Splicing Not identified NA a Mutation which is presumed to be in linkage disequilibrium with unknown pathologic ABCA4 mutation. Login to comment
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
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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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] Mutation spectrum and founder chromosomes for the ... Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1705-11. September AV, Vorster AA, Ramesar RS, Greenberg LJ
Mutation spectrum and founder chromosomes for the ABCA4 gene in South African patients with Stargardt disease.
Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1705-11., [PMID:15161829]

Abstract [show]
PURPOSE: To assess the mutation spectrum of ABCA4 underlying Stargardt disease (STGD) in South Africa (SA) and to determine whether there is a single or a few founder chromosomes in SA STGD families. METHODS: Sixty-four probands exhibiting the STGD phenotype were screened for mutations in the 50 exons of ABCA4 by single-strand conformational polymorphism-heteroduplex analysis sequencing and restriction fragment length polymorphism analysis. Microsatellite marker haplotyping was used to determine the ancestry in 10 families. RESULTS: Fifty-seven ABCA4 disease-associated alleles were identified that comprised 16 different sequence variants, of which two were novel, in 40 individuals of the cohort of 64 subjects. The most common variants identified included the C1490Y, L2027F, R602W, V256splice, R152X, and 2588G-->C mutations. The C1490Y variant was the most common disease-associated variant identified (19/64 subjects) and was absent in 392 control chromosomes. At least 10 ABCA4 disease-associated haplotypes were identified. Two of these haplotypes, which carried the C1490Y mutation, were identified in three unrelated families. CONCLUSIONS: Results suggest that ABCA4 is the major gene underlying STGD in the cohort investigated. Five of the six common sequence variants identified were at a higher frequency in the SA cohort than reported in published data on individuals of similar ancestry. The mutation and haplotype data suggests that there are several ancestral haplotypes underlying STGD in SA. There seems to be at least two different origins for the common C1490Y mutation, as well as two for the R602W mutation, thereby suggesting several founder effects for STGD in SA.

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114 The 14 Non-Disease-Causing Sequence Variants Identified in the Study Nucleotide Change Amino Acid Change Families (n ‫؍‬ 64) G1009C E310Q 2 G989A G330D 1 IVS18-38⌬G - 3 G2828A R943Q 6 C4184T P1395L 1 IVS27-71T3A - 1 IVS28-38G3A - 1 IVS38-10T3C - 1 IVS39-17T3A - 1 G5682C L1894L 1 TG5925CA L1984L 2 IVS43-16G3A - 3 C6329T 12083I 1 G6355A E2119K 2 other ABCA4 studies in which similar mutation screening methods were used.10,11,26 -28 Methods such as direct sequencing of all arSTGD probands in other studies have, however, identified approximately 66% to 80% of ABCA4-associated STGD chromosomes.13,14 The SSCP-HD mutation screening method used in this study has a reported sensitivity of 97%.17 It is possible that allelic mutations have been missed because (1) of the sensitivity of the method used, or (2) the unidentified mutations may reside in parts of the gene-for example, the promotor or regulatory regions that have not yet been screened. Login to comment

[hide] Genotyping microarray (gene chip) for the ABCR (AB... Hum Mutat. 2003 Nov;22(5):395-403. Jaakson K, Zernant J, Kulm M, Hutchinson A, Tonisson N, Glavac D, Ravnik-Glavac M, Hawlina M, Meltzer MR, Caruso RC, Testa F, Maugeri A, Hoyng CB, Gouras P, Simonelli F, Lewis RA, Lupski JR, Cremers FP, Allikmets R
Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.
Hum Mutat. 2003 Nov;22(5):395-403., [PMID:14517951]

Abstract [show]
Genetic variation in the ABCR (ABCA4) gene has been associated with five distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), and age-related macular degeneration (AMD). Comparative genetic analyses of ABCR variation and diagnostics have been complicated by substantial allelic heterogeneity and by differences in screening methods. To overcome these limitations, we designed a genotyping microarray (gene chip) for ABCR that includes all approximately 400 disease-associated and other variants currently described, enabling simultaneous detection of all known ABCR variants. The ABCR genotyping microarray (the ABCR400 chip) was constructed by the arrayed primer extension (APEX) technology. Each sequence change in ABCR was included on the chip by synthesis and application of sequence-specific oligonucleotides. We validated the chip by screening 136 confirmed STGD patients and 96 healthy controls, each of whom we had analyzed previously by single strand conformation polymorphism (SSCP) technology and/or heteroduplex analysis. The microarray was >98% effective in determining the existing genetic variation and was comparable to direct sequencing in that it yielded many sequence changes undetected by SSCP. In STGD patient cohorts, the efficiency of the array to detect disease-associated alleles was between 54% and 78%, depending on the ethnic composition and degree of clinical and molecular characterization of a cohort. In addition, chip analysis suggested a high carrier frequency (up to 1:10) of ABCR variants in the general population. The ABCR genotyping microarray is a robust, cost-effective, and comprehensive screening tool for variation in one gene in which mutations are responsible for a substantial fraction of retinal disease. The ABCR chip is a prototype for the next generation of screening and diagnostic tools in ophthalmic genetics, bridging clinical and scientific research.

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88 Several common polymorphisms were also included, mainly from the coding region (R212H, H423R, R943Q, N1868I, P1948L, S2255I). Login to comment
102 R943Q, as a frequent polymorphism, is not counted in the disease-associated alleles row. Login to comment
115 Mutations Detected in theTwoTest Populations by the ABCR400 Array,That Had Not Been Found by SSCP Number Nucleotide change Protein e¡ect Number of cases 1 161G4A C54Y 3 2 194G4A G65E 1 3 428C4T P143L 1 4 455G4A R152Q 1 5 514G4A G172S 1 6 635G4A R212H 1 7 656G4C R219T 1 8 768G4Ta Splice/V256V 3 9 1007C4G S336C 2 10 1268A4G H423R 4 11 1411G4A E471K 2 12 1622T4Ca L541P 8 13 1933G4A D645N 1 14 2041C4T R681X 5 15 2090G4A W697X 1 16 2471T4C I824T 1 17 2588G4Ca Splice/G863A 5 18 2828G4A R943Q 1 19 2966T4C V989A 1 20 2971G4C G991R 1 21 4139C4T P1380L 8 22 4195G4A E1399K 1 23 4328G4A R1443H 1 24 4457C4T P1486L 1 25 4462T4Ca C1488R 1 26 4469G4Aa C1490Y 1 27 4918C4Ta R1640W 2 28 IVS40+5G4A Splice 2 29 5537T4C I1846T 2 30 5882G4A G1961E 5 31 6089G4A R2030Q 1 32 6104T4C L2035P 1 33 6449G4A C2150Y 1 Mutation numbering is based on the cDNA sequence (GenBank NM_000350). Login to comment

[hide] Macular pigment and visual acuity in Stargardt mac... Graefes Arch Clin Exp Ophthalmol. 2002 Oct;240(10):802-9. Epub 2002 Sep 14. Zhang X, Hargitai J, Tammur J, Hutchinson A, Allikmets R, Chang S, Gouras P
Macular pigment and visual acuity in Stargardt macular dystrophy.
Graefes Arch Clin Exp Ophthalmol. 2002 Oct;240(10):802-9. Epub 2002 Sep 14., [PMID:12397427]

Abstract [show]
PURPOSE: To test the hypothesis that macular pigment reflects foveal cone function and possibly the presence of foveal cones in recessive Stargardt macular dystrophy. METHODS: Sixteen patients (32 eyes) diagnosed to have Stargardt macular dystrophy by clinical criteria were studied with a scanning laser ophthalmoscope (SLO) comparing argon laser blue (488 nm), green (514), helium-neon laser red (633 nm) and infrared diode laser (780 nm) images for the presence or absence of macular pigment in the fovea. Fifteen of the patients were screened for mutations in the ABCR gene. Eyes were graded into three categories: those without foveal macular pigment, those with partial pigment and those with normal amounts of macular pigment. These categories were compared with visual acuity determined by the Snellen chart. RESULTS: All patients with a visual acuity of 20/200 or worse had no macular pigment in the fovea. All patients with visual acuity of 20/40 or better had a normal amount of macular pigment in the fovea. Patients with partial macular pigment had intermediary acuity values except for two eyes, one with 20/20 and another with 20/200 acuity. Infrared light revealed more retinal abnormalities than blue light at early stages of the disease. CONCLUSION: Foveal macular pigment is related to foveal cone acuity in Stargardt macular dystrophy and may be a marker for the presence of foveal cones. Infrared light is a sensitive monitor of early Stargardt macular dystrophy.

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54 Blue light images (A, C); infrared images (B, D) Table 1 Visual acuity, macular pigment and ABCR mutations in patients with Stargardt dystrophy Patient Age/Sex Visual Acuity Macular Pigment Exon Allele 1 Exon Allele 2 OD OS OD OS 1 33F 0.67 0.38 + + ND ND 2 36F 1 0.5 + + ND ND 3 54F 0.48 0.6 + + 42 G1961E 42 G1061E 4 11M 0.8 1 + + NS NS 5 33F 0.67 0.4 +- + 20 V989A ND 6 12F 0.5 0.2 +- +- 30 C1490Y 40 GIVS+5A 7 47M 0.5 0.4 +- +- 17 G863A/R943Q 45 R2077W 8 53M 0.1 1 +- +- 14 W663X ND 9 29F 0.1 0.1 +- +- 26 3819insT ND 10 43M 0.005 0.005 - - 17 G863A/R943Q ND 11 32F 0.1 0.1 - - 19 N965S ND 12 29F 0.005 0.005 - - 23 R1129H ND 13 30F 0.1 0.1 - - 5 R152Q ND 14 63F 0.1 0.1 - - 42 G1961E ND 15 36M 0.07 0.1 - +- 13 Q636H 42 G1961E 16 41F 0.005 0.005 - - 12 L514P/A1038V ND NS: Not screened; ND: Not detected + Normal macular pigment; +- Partial macular pigment; - Absent macular pigment absorption of infrared light in the center of the macula where maximum absorption of blue light occurs, implying that the macula pigments in this subject`s foveas are normal. Login to comment

[hide] Biochemical defects in retina-specific human ATP b... J Biol Chem. 2002 Jun 14;277(24):21759-67. Epub 2002 Mar 27. Suarez T, Biswas SB, Biswas EE
Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration.
J Biol Chem. 2002 Jun 14;277(24):21759-67. Epub 2002 Mar 27., [PMID:11919200]

Abstract [show]
The retina-specific human ABC transporter (ABCR) functions in the retinal transport system and has been implicated in several inherited visual diseases, including Stargardt disease, fundus flavimaculatus, cone-rod dystrophy, and age-related macular degeneration. We have previously described a general ribonucleotidase activity of the first nucleotide binding domain (NBD1) of human ABCR (Biswas, E. E. (2001) Biochemistry 40, 8181-8187). In this communication, we present a quantitative study analyzing the effects of certain disease-associated mutations, Gly-863 --> Ala, Pro-940 --> Arg, and Arg-943 --> Gln on the nucleotide binding, and general ribonucleotidase activities of this domain. NBD1 proteins, harboring these mutations, were created through in vitro site-specific mutagenesis and expressed in Escherichia coli. Results of the enzyme-kinetic studies indicated that these mutations altered the ATPase and CTPase activities of NBD1. The G863A and P940R mutations were found to have significant attenuation of the rates of nucleotide hydrolysis and binding affinities. On the other hand, the R943Q mutation had small, but detectable reduction in its nucleotidase activity and nucleotide binding affinity. We have measured the nucleotide binding affinities of NBD1 protein and its mutants quantitatively by fluorescence anisotropy changes during protein binding to ethenoadenosine ATP (epsilonATP), a fluorescent ATP analogue. We have correlated the dissociation constant (K(D)) and the rates of nucleotide hydrolysis (V(max)) of NBD1 and its mutants with the available genetic data for these mutations.

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6 On the other hand, the R943Q mutation had small, but detectable reduction in its nucleotidase activity and nucleotide binding affinity. Login to comment
139 Equal amounts of cells before and after induction were analyzed by 5-18% SDS-PAGE followed by Coomassie Blue R-250 staining: lanes 1 and 2, BL21(DE3)/pET29aNBD1 wild-type cells before and after induction, respectively; lane 3, BL21(DE3)/pET29aNBD1/ G863A cells before induction, and after induction in lane 4; lanes 5 and 6, BL21(DE3)/pET29aNBD1/P940R cells before induction and after induction, respectively; lane 7, BL21(DE3)/pET29aNBD1/R943Q cells before induction and lane 8 after induction. Login to comment
141 Lane 1, wild-type NBD1 protein; lane 2, NBD1/G863A mutant protein; lane 3, NBD1/P940R mutant protein; and lane 4, NBD1/R943Q mutant protein. Login to comment
168 Standard ATP assays were carried out as described under "Materials and Methods" at 37 °C for the times indicated using [␣-32 P]ATP and 2.5 ␮g of purified NBD1 wild-type and NBD1/P940R proteins. Login to comment
169 NBD1 wild-type (Ⅺ) and P940R mutant (‚;). Login to comment
171 Nucleotidase activities of R943Q mutant protein. Login to comment
172 A, comparison of ATP hydrolysis by NBD1wt and NBD1/R943Q polypeptides. Login to comment
173 The protein titration of purified NBD1/R943Q and NBD1 wild-type proteins was performed in a standard ATPase assay as described under "Materials and Methods." Login to comment
174 The assays were carried out at 37 °C for 60 min using the indicate amounts of protein and ATP concentration of 500 ␮M. B, hydrolysis of CTP by wtNBD1 and the mutant-R943Q. Login to comment
175 Protein titration of purified NBD1 wild-type and NBD1/R943Q proteins in a standard CTPase assay was carried out as described under "Materials and Methods" at 37 °C for 60 min using the indicated amounts of protein and CTP concentration of 500 ␮M. C, time-course analysis of ATP hydrolysis. Standard ATP assays were carried out as described under "Materials and Methods" at 37 °C for the times indicated using [␣-32 P]ATP and 2.5 ␮g of purified wild-type and R943Q proteins. Login to comment
176 NBD1 wild-type (Ⅺ) and R943Q mutant (●). Login to comment
184 Arg-943 3 Gln Is the Least Influential on ATP and CTP Hydrolysis of NBD1wt Protein-The amino acid change R943Q has been described as a polymorphism, because it has been found in control populations (5, 9-11, 14). Login to comment
188 The Vmax for R943Q mutant was 392 pmol/min/mg, and that of the wild-type NBD1 was 584 pmol/min/mg (Table II). Login to comment
189 The time-course analysis of ATPase activity (Fig. 5C), suggested that the ATPase activity of R943Q protein function was about 40% reduced with respect to that observed for NBD1wt. Login to comment
190 The Vmax for R943Q mutant was 172 pmol/min/mg and that of the wild-type NBD1 was 376 pmol/min/mg (Table II). Login to comment
191 Therefore, the CTPase activity of R943Q was reduced 2-fold compared with that observed with wild-type NBD1 (Fig. 5), indicating a higher inhibitory effect of this mutation on the CTPase (ϳ57%) than ATPase (ϳ12%) activity. Login to comment
197 The rate of ATP hydrolysis was also altered and the Vmax values were 392 (R943Q), 129 (G863A), and 128 (P940R) pmol/min/mg. Login to comment
198 This represented a 78% decrease in Vmax for the G863A and P940R mutants, whereas the Vmax for R943Q mutant was diminished by only 33%. Login to comment
211 The plots, shown in Fig. 7, were generated by TABLE II Thermodynamic and kinetic parameters of ATP binding and hydrolysis for wild-type and mutant NBD1 proteins Parameter Wild-type R943Q P940R G863A Enzyme kinetics Vmax (pmol/min/mg) ATP 584 392 129 128 CTP 376 172 84 104 ATP binding ⌬G ° (kcal/mol) -8.2 -8.6 -8.1 -7.6 KD (M) 9.9 ϫ 10-7 5 ϫ 10-7 1.2 ϫ10-6 2.7 ϫ 10-6 Inhibition (%) ATP 0 33 78 78 CTP 0 54 78 72 Disease severity - ϩ/- ϩϩ ϩϩ FIG. 6. Login to comment
219 NBD1 wild-type (Ⅺ), mutant G863A (E), mutant P940R (‚), and mutant R943Q (●). Login to comment
222 This nonlinear regression analysis gave dissociation constants (KD) for each of these proteins as follows: 9.9 ϫ 10-7 , 2.7 ϫ 10-6 , 1.2 ϫ 10-6 , and 5 ϫ 10-7 M, and ⌬G ϭ -8.2, -7.6, -8.1, and -8.6 kcal/mol for wild-type protein, G863A, P940R, and R943Q, respectively. Login to comment
224 The binding capacity of R943Q was comparable to wild-type. Login to comment
231 We have generated a model for the NBD1 domain of ABCR (Fig. 9) using the Swiss-PDB and SYBYL6.7 homology-based protein structure modeling software to delineate the G863A, P940R, and R943Q mutations and analyze the possible structural implications on the wild-type NBD1 structure. Login to comment
243 Using refolded and highly purified and homogeneous preparations of wild-type, G863A, P940R, and R943Q NBD1 proteins (Fig. 2), we were able to examine the biochemical consequences of these mutations on the nucleotide binding and hydrolysis activity of FIG. 7. Login to comment
248 D, NBD1/R943Q mutant ({). Login to comment
253 The data were fitted with BIOEQS using a simple binding model (monomer) for ⑀ATP binding to wild-type, G863A, P940R, and R943Q NBD1 proteins. Login to comment
274 We have carried out a detailed kinetic analysis of P940R mutant of NBD1. Login to comment
277 In general, both the G863A and P940R mutations were comparable in attenuating the nucleotidase activities. Login to comment
279 The ATPase activity of the R943Q mutant protein was diminished, although the extent of diminution was not as great as that observed with G863A or P940R (Figs. 3-5, Table II). Login to comment
281 Overall, the enzymatic activity of mutants G863A and P940R was reduced more than that of the R943Q mutant, and the results on the nucleotide binding and hydrolysis correlate well with frequency and disease severity. Login to comment
282 Effects of G863A, P940R, and R943Q Mutations on the ⑀ATP Binding to NBD1 Protein-The biochemical effects in ATPase could be due to defects in nucleotide binding or hydrolysis or both. Login to comment
287 The results indicated that dissociation constants for both wild-type and R943Q nonpathogenic mutation were comparable, and the values were 9.9 ϫ 10-7 M and 5 ϫ 10-7 M, respectively. Login to comment
288 In fact, the dissociation constant for R943Q was lower than that of the wild-type. Login to comment
290 The overall order of nucleotide binding affinity was: R943Q Ͼ wild-type Ͼ P940R Ͼ G863A. Login to comment
291 The values for the free energy change involved in nucleotide binding (⌬G°) were as follows: -8.2 (wild-type), -8.6 (R943Q), -8.1 (P940R), and -7.6 (G863A) kcal/mole, respectively. Login to comment
301 The G863A mutation has been reported as one of the most frequently observed mutations in STGD patients in North America (2) and Netherlands (12). Login to comment
306 The R943Q mutation displayed the minimal defects in nucleotide binding. Login to comment
310 The R943Q mutation has also been shown to occur in conjunction with G863A leading to a more severe pathogenic state in humans (45). Login to comment
313 The model illustrates the spatial distribution of the amino acid changes of Pro-940 for arginine, and Arg-943 for glutamine, as well as the location of the Walker A and B motifs. Login to comment
317 In the case of the R943Q mutation, the change of a polar amino acid to a neutral amino acid may be less disruptive structurally. Login to comment
136 Equal amounts of cells before and after induction were analyzed by 5-18% SDS-PAGE followed by Coomassie Blue R-250 staining: lanes 1 and 2, BL21(DE3)/pET29aNBD1 wild-type cells before and after induction, respectively; lane 3, BL21(DE3)/pET29aNBD1/ G863A cells before induction, and after induction in lane 4; lanes 5 and 6, BL21(DE3)/pET29aNBD1/P940R cells before induction and after induction, respectively; lane 7, BL21(DE3)/pET29aNBD1/R943Q cells before induction and lane 8 after induction. Login to comment
138 Lane 1, wild-type NBD1 protein; lane 2, NBD1/G863A mutant protein; lane 3, NBD1/P940R mutant protein; and lane 4, NBD1/R943Q mutant protein. Login to comment
170 The protein titration of purified NBD1/R943Q and NBD1 wild-type proteins was performed in a standard ATPase assay as described under "Materials and Methods." Login to comment
181 Arg-943 3 Gln Is the Least Influential on ATP and CTP Hydrolysis of NBD1wt Protein-The amino acid change R943Q has been described as a polymorphism, because it has been found in control populations (5, 9-11, 14). Login to comment
185 The Vmax for R943Q mutant was 392 pmol/min/mg, and that of the wild-type NBD1 was 584 pmol/min/mg (Table II). Login to comment
186 The time-course analysis of ATPase activity (Fig. 5C), suggested that the ATPase activity of R943Q protein function was about 40% reduced with respect to that observed for NBD1wt. Login to comment
187 The Vmax for R943Q mutant was 172 pmol/min/mg and that of the wild-type NBD1 was 376 pmol/min/mg (Table II). Login to comment
194 The rate of ATP hydrolysis was also altered and the Vmax values were 392 (R943Q), 129 (G863A), and 128 (P940R) pmol/min/mg. This represented a 78% decrease in Vmax for the G863A and P940R mutants, whereas the Vmax for R943Q mutant was diminished by only 33%. Login to comment
207 The plots, shown in Fig. 7, were generated by TABLE II Thermodynamic and kinetic parameters of ATP binding and hydrolysis for wild-type and mutant NBD1 proteins Parameter Wild-type R943Q P940R G863A Enzyme kinetics Vmax (pmol/min/mg) ATP 584 392 129 128 CTP 376 172 84 104 ATP binding èc;G &#b0; (kcal/mol) afa;8.2 afa;8.6 afa;8.1 afa;7.6 KD (M) 9.9 afb; 10afa;7 5 afb; 10afa;7 1.2 afb;10afa;6 2.7 afb; 10afa;6 Inhibition (%) ATP 0 33 78 78 CTP 0 54 78 72 Disease severity afa; af9;/afa; af9;af9; af9;af9; FIG. 6. Login to comment
215 NBD1 wild-type (ǧa;), mutant G863A (E), mutant P940R (Éa;), and mutant R943Q (cf;). Login to comment
218 This nonlinear regression analysis gave dissociation constants (KD) for each of these proteins as follows: 9.9 afb; 10afa;7 , 2.7 afb; 10afa;6 , 1.2 afb; 10afa;6 , and 5 afb; 10afa;7 M, and èc;G afd; afa;8.2, afa;7.6, afa;8.1, and afa;8.6 kcal/mol for wild-type protein, G863A, P940R, and R943Q, respectively. Login to comment
220 The binding capacity of R943Q was comparable to wild-type. Login to comment
227 We have generated a model for the NBD1 domain of ABCR (Fig. 9) using the Swiss-PDB and SYBYL6.7 homology-based protein structure modeling software to delineate the G863A, P940R, and R943Q mutations and analyze the possible structural implications on the wild-type NBD1 structure. Login to comment
239 Using refolded and highly purified and homogeneous preparations of wild-type, G863A, P940R, and R943Q NBD1 proteins (Fig. 2), we were able to examine the biochemical consequences of these mutations on the nucleotide binding and hydrolysis activity of FIG. 7. Login to comment
244 D, NBD1/R943Q mutant ({). Login to comment
249 The data were fitted with BIOEQS using a simple binding model (monomer) for ঈATP binding to wild-type, G863A, P940R, and R943Q NBD1 proteins. Login to comment
276 Overall, the enzymatic activity of mutants G863A and P940R was reduced more than that of the R943Q mutant, and the results on the nucleotide binding and hydrolysis correlate well with frequency and disease severity. Login to comment
283 In fact, the dissociation constant for R943Q was lower than that of the wild-type. Login to comment
285 The overall order of nucleotide binding affinity was: R943Q b0e; wild-type b0e; P940R b0e; G863A. Login to comment
286 The values for the free energy change involved in nucleotide binding (èc;G&#b0;) were as follows: afa;8.2 (wild-type), afa;8.6 (R943Q), afa;8.1 (P940R), and afa;7.6 (G863A) kcal/mole, respectively. Login to comment
305 The R943Q mutation has also been shown to occur in conjunction with G863A leading to a more severe pathogenic state in humans (45). Login to comment
308 The model illustrates the spatial distribution of the amino acid changes of Pro-940 for arginine, and Arg-943 for glutamine, as well as the location of the Walker A and B motifs. Login to comment
312 In the case of the R943Q mutation, the change of a polar amino acid to a neutral amino acid may be less disruptive structurally. Login to comment

[hide] The ABCA4 2588G>C Stargardt mutation: single origi... Eur J Hum Genet. 2002 Mar;10(3):197-203. Maugeri A, Flothmann K, Hemmrich N, Ingvast S, Jorge P, Paloma E, Patel R, Rozet JM, Tammur J, Testa F, Balcells S, Bird AC, Brunner HG, Hoyng CB, Metspalu A, Simonelli F, Allikmets R, Bhattacharya SS, D'Urso M, Gonzalez-Duarte R, Kaplan J, te Meerman GJ, Santos R, Schwartz M, Van Camp G, Wadelius C, Weber BH, Cremers FP
The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe.
Eur J Hum Genet. 2002 Mar;10(3):197-203., [PMID:11973624]

Abstract [show]
Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.

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38 Haplotype analysis in 16 families segregating the 2588G4C mutation, showed four intragenic polymorphisms, ie 2828G4A (R943Q), 4203C4A (P1401P), 5603A4T Table 1 Occurrence of the 2588G4C ABCA4 mutation in 11 European countries and the US Controls STGDa No. 2588C alleles/No. chromosomes (%) Carrier frequency No. 2588C alleles/No. chromosomes (%) Sweden 11 out of 394 (2.8) 1 out of 18 The Netherlands 9 out of 622 (1.4)b 1 out of 35 22 out of 126 (17.5) Estonia 4 out of 390 (1.0) 1 out of 49 Denmark 2 out of 200 (1.0) 1 out of 50 10 out of 98 (10.2) Italy 4 out of 400 (1.0) 1 out of 50 Germany 5 out of 672 (0.7) 1 out of 67 21 out of 310 (6.8) France 3 out of 434 (0.7) 1 out of 72 7 out of 254 (2.8) UK 2 out of 352 (0.6)c 1 out of 88 5 out of 140 (3.6)c Belgium 2 out of 406 (0.5) 1 out of 102 Spain 1 out of 418 (0.2)d 1 out of 209 Portugal 0 out of 398 (0.0) 0 out of 199 Total Europe 43 out of 4686 (0.9) 1 out of 54 65 out of 928 (7.0) US 2 out of 482 (0.4) 1 out of 121 11 out of 300 (3.7)e a Frequencies were calculated only when more than 80 chromosomes were analysed. Login to comment

[hide] Null missense ABCR (ABCA4) mutations in a family w... Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2757-61. Shroyer NF, Lewis RA, Yatsenko AN, Lupski JR
Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa.
Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2757-61., [PMID:11687513]

Abstract [show]
PURPOSE: To determine the type of ABCR mutations that segregate in a family that manifests both Stargardt disease (STGD) and retinitis pigmentosa (RP), and the functional consequences of the underlying mutations. METHODS: Direct sequencing of all 50 exons and flanking intronic regions of ABCR was performed for the STGD- and RP-affected relatives. RNA hybridization, Western blot analysis, and azido-adenosine triphosphate (ATP) labeling was used to determine the effect of disease-associated ABCR mutations in an in vitro assay system. RESULTS: Compound heterozygous missense mutations were identified in patients with STGD and RP. STGD-affected individual AR682-03 was compound heterozygous for the mutation 2588G-->C and a complex allele, [W1408R; R1640W]. RP-affected individuals AR682-04 and-05 were compound heterozygous for the complex allele [W1408R; R1640W] and the missense mutation V767D. Functional analysis of the mutation V767D by Western blot and ATP binding revealed a severe reduction in protein expression. In vitro analysis of ABCR protein with the mutations W1408R and R1640W showed a moderate effect of these individual mutations on expression and ATP-binding; the complex allele [W1408R; R1640W] caused a severe reduction in protein expression. CONCLUSIONS: These data reveal that missense ABCR mutations may be associated with RP. Functional analysis reveals that the RP-associated missense ABCR mutations are likely to be functionally null. These studies of the complex allele W1408R; R1640W suggest a synergistic effect of the individual mutations. These data are congruent with a model in which RP is associated with homozygous null mutations and with the notion that severity of retinal disease is inversely related to residual ABCR activity.

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102 ABCR Alterations in Patients with Stargardt Disease and Retinitis Pigmentosa Exon Nucleotide Amino Acid AR682-03 AR682-04 3 302ϩ26 A/A A/G 10 1268G 3 A H423R A/A A/G 1356ϩ11delG 6G/6G 6G/7G 15 2300T 3 A V767D T/T T/A 17 2588G 3 C G863A G/C G/G 19 2828G 3 A R943Q G/A G/G 24 3523-30 A/T A/T 28 4203C 3 A P1401P C/A C/C 4222T 3 C W1408R C/T C/T 33 4667ϩ48 C/T T/T 35 4918C 3 T R1640W C/T C/T 40 5585-70 C/T T/T 5603A 3 T N1868I A/T A/A 5682G 3 C L1894L G/C G/G Mutations are indicated in bold. Login to comment
101 ABCR Alterations in Patients with Stargardt Disease and Retinitis Pigmentosa Exon Nucleotide Amino Acid AR682-03 AR682-04 3 302af9;26 A/A A/G 10 1268G 3 A H423R A/A A/G 1356af9;11delG 6G/6G 6G/7G 15 2300T 3 A V767D T/T T/A 17 2588G 3 C G863A G/C G/G 19 2828G 3 A R943Q G/A G/G 24 3523-30 A/T A/T 28 4203C 3 A P1401P C/A C/C 4222T 3 C W1408R C/T C/T 33 4667af9;48 C/T T/T 35 4918C 3 T R1640W C/T C/T 40 5585-70 C/T T/T 5603A 3 T N1868I A/T A/A 5682G 3 C L1894L G/C G/G Mutations are indicated in bold. Login to comment

[hide] Different clinical expressions in two families wit... Acta Ophthalmol Scand. 2001 Oct;79(5):524-30. Eksandh L, Ekstrom U, Abrahamson M, Bauer B, Andreasson S
Different clinical expressions in two families with Stargardt's macular dystrophy (STGD1).
Acta Ophthalmol Scand. 2001 Oct;79(5):524-30., [PMID:11594993]

Abstract [show]
PURPOSE: To describe the clinical expressions, with emphasis on electrophysiological examinations, in two Swedish families with Stargardt's macular dystrophy (STGD1). METHODS: Two pairs of siblings with STGD1, for whom diagnosis had been confirmed by genetic linkage to the ABCA4 gene region, were examined regarding visual acuity, kinetic perimetry, fundus photography, full-field ERG and multifocal ERG (MERG). Possible disease-causing mutations were screened for by DNA sequencing of selected regions of the ABCA4 gene. RESULTS: All STGD1 patients had visual acuity 0.07-0.1. The two families presented different fundus appearances, MERGs and implicit times on 30 Hz flicker white light full-field ERGs. Genetic analysis revealed one unique sequence variation in exon 19 of the ABCA4 gene, in one allele from the patients of one of the families. This point mutation causes the amino acid substitution T972N in the ABCR protein. CONCLUSION: Two pairs of siblings with STGD1 presented two different expressions of the disease regarding the distribution of the retinal dysfunction. One possible molecular explanation to the different clinical expressions may be the T972N substitution present in the ABCR protein in one of the STGD1 families investigated.

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98 So have the alterations found in exon 42, 5843CA»TG causing the substitution P1948L, and the 2828G»A mutation in exon 19 causing R943Q at the protein level (Table 3). Login to comment
111 DNA AII:1 AII:2 BII:1 BII:2 Locus alteration Effect STGD STGD AI:1 AI:2 STGD STGD BI:1 BI:2 Comments In 18 IVS18-38delC ª delC/delC delC/delC delC/delC DelC/delC delC/delC delC/delC delC/delC delC/delC Ex 19 2828G-ϾA R943Q G/A G/A G/G G/A G/G G/G G/G G/G Polymorphism1 Ex 19 2915C-ϾA T972N C/C C/C C/C C/C C/A C/A C/C C/A Disease-associated? Login to comment

[hide] Mutations in ABCR (ABCA4) in patients with Stargar... Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2229-36. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP
Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.
Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2229-36., [PMID:11527935]

Abstract [show]
PURPOSE: To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone-rod degeneration (CRD). METHODS: One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified. RESULTS: The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes. CONCLUSIONS: This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

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64 Gly863Ala was detected in 9 of 252 patient alleles and 2 of 380 normal control alleles tested (P ϭ 0.009), and it was also considered pathogenic. Login to comment
65 Four missense changes, Arg212His, His423Arg, Arg943Gln, and Pro1948Leu, were found at approximately equal frequency among patients and normal control subjects (P Ͼ 0.05 by Fisher`s two-tailed analysis) and were thus categorized as nonpathogenic polymorphisms. Login to comment
116 Nucleotide 2588G 3C (Gly863Ala) and Nucleotide 2828G3A (Arg943Gln) One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. Login to comment
117 In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Login to comment
118 Maugeri et al.21 also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. Login to comment
119 In our study, the Arg943Gln change was present in five other patients without Gly863Ala, and it was present without Gly863Ala in 9 of 190 control alleles. Login to comment
120 In addition, a recently reported evaluation of the Gly863Ala mutant protein has shown that it has abnormal function in vitro.26 Taken together, these results indicate that Gly863Ala by itself is likely to be pathogenic and Arg943Gln by itself is not. Login to comment
113 Nucleotide 2588G 3C (Gly863Ala) and Nucleotide 2828G3A (Arg943Gln) One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. Login to comment
114 In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Login to comment
115 Maugeri et al.21 also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. Login to comment

[hide] Spectrum of ABCA4 (ABCR) gene mutations in Spanish... Hum Mutat. 2001 Jun;17(6):504-10. Paloma E, Martinez-Mir A, Vilageliu L, Gonzalez-Duarte R, Balcells S
Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies.
Hum Mutat. 2001 Jun;17(6):504-10., [PMID:11385708]

Abstract [show]
The ABCA4 gene has been involved in several forms of inherited macular dystrophy. In order to further characterize the complex genotype-phenotype relationships involving this gene, we have performed a mutation analysis of ABCA4 in 14 Spanish patients comprising eight STGD (Stargardt), four FFM (fundus flavimaculatus), and two CRD (Cone-rod dystrophy) patients. SSCP (single-strand conformation polymorphism) analysis and DNA sequencing of the coding and 5' upstream regions of this gene allowed the identification of 16 putatively pathogenic alterations, nine of which are novel. Most of these were missense changes, and no patient was found to carry two null alleles. Overall, the new data agree with a working model relating the different pathogenic phenotypes to the severity of the mutations. When considering the information presented here together with that of previous reports, a picture of the geographic distribution of three particular mutations emerges. The R212C change has been found in French, Italian, Dutch, German, and Spanish but not in British patients. In the Spanish collection, R212C was found in a CRD patient, indicating that it may be a rather severe change. In contrast, c.2588G>C, a very common mild allele in the Dutch population, is rarely found in Southern Europe. Interestingly, the c.2588G>C mutation has been found in a double mutant allele together with the missense R1055W. Finally, the newly described L1940P was found in two unrelated Spanish patients, and may be a moderate to severe allele.

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77 These comprise two missense changes found also in control chromosomes that were described as polymorphisms by other authors (R943Q and S2255I). Login to comment
80 We examined the genomic sequences surrounding each of the changes looking for cryptic splice sites, and none was found, with the exception of c.1356+ TABLE 2. Summary of the Putative Polymorphisms Found in the Screening of the ABCA4 Gene Nucleotide change Exon/IVS Amino acid change No. of patients No. of controls Referencesa c.1239-14T->C IVS9 1 NT c.1239-63insC IVS9 1 NT c.1356+11delG IVS10 1 7/140 1 c.1762-54G->A IVS12 2 NT c.2829G->A E19 R943Q 1 8/70 2 c.3863-110G->C IVS26 1 0/50 c.4284G->A E29 T1466T 1 0/50 c.5461-50insA IVS38 1 NT c.5584+11C->G IVS39 1 NT c.5715-25C->A IVS40 1 NT c.5844A->G E42 P1948P 1 5/29 3 c.5843CA->TG E42 P1948L 1 NT 3 c.5835-43A->C IVS41 1 NT c.5835-11A->G IVS41 1 NT c.6249C->T E45 I2083I 2 NT 2 c.6285T->C E46 D2095D 1 NT 3 c.6480-21C->T IVS47 1 0/51 c.6730-5A->C IVS48 1 3/50 c.6764G->T E49 S2255I 2 6/26 2 c.6816+28G->C IVS49 1 4/14 a References: 1, Papaioannou et al. [2000]; 2, Allikmets et al. [1997]; 3, Maugeri et al. [1999]. 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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109 If the three most common missense variants (Asn1868Ile, Ser2255Ile, and Arg943Gln) were not included, missense variants were detected in 34 (9.3%) of 364 AMD alleles and 13 (6.7%) of 192 control alleles. Login to comment
130 However, the nonconservative subset was not more strongly associated with Stargardt disease than the conservative subset, largely because three of the nonconservative changes exhibited a prevalence in non-Stargardt alleles of more than 4% (Asn1868Ile, Arg943Gln, and Ser2255Ile). Login to comment
152 These included two common polymorphisms Arg943Gln and Pro1948Leu that occurred on more than 3% of all alleles. Login to comment
173 Furthermore, the missense changes Gly863Ala and Arg943Gln were commonly found together. Login to comment
175 However, linkage disequilibrium was not complete, because the rarer Gly863Ala change occurred by itself in three patients with Stargardt disease. Login to comment
237 For example, Arg943Gln is present in more than 6% of the normal population. If it were an HPRDCV, it alone would be expected to cause disease in more than 1 in 300 individuals, a rate that is 30 times higher than the prevalence of Stargardt disease in the population. If, on the other hand, Arg943Gln is a low-penetrance recessive DCV that is incapable of causing disease in the homozygous state but is capable of contributing to the disease phenotype when paired with certain rare HPRDCVs, this variant alone would increase our DCV detection rate by approximately 5%. Login to comment
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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110 If the three most common missense variants (Asn1868Ile, Ser2255Ile, and Arg943Gln) were not included, missense variants were detected in 34 (9.3%) of 364 AMD alleles and 13 (6.7%) of 192 control alleles. Login to comment
131 However, the nonconservative subset was not more strongly associated with Stargardt disease than the conservative subset, largely because three of the nonconservative changes exhibited a prevalence in non-Stargardt alleles of more than 4% (Asn1868Ile, Arg943Gln, and Ser2255Ile). Login to comment
153 These included two common polymorphisms Arg943Gln and Pro1948Leu that occurred on more than 3% of all alleles. Login to comment
239 For example, Arg943Gln is present in more than 6% of the normal population. If it were an HPRDCV, it alone would be expected to cause disease in more than 1 in 300 individuals, a rate that is 30 times higher than the prevalence of Stargardt disease in the population. If, on the other hand, Arg943Gln is a low-penetrance recessive DCV that is incapable of causing disease in the homozygous state but is capable of contributing to the disease phenotype when paired with certain rare HPRDCVs, this variant alone would increase our DCV detection rate by approximately 5%. Login to comment

[hide] Late-onset Stargardt disease is associated with mi... Hum Genet. 2001 Apr;108(4):346-55. Yatsenko AN, Shroyer NF, Lewis RA, Lupski JR
Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4).
Hum Genet. 2001 Apr;108(4):346-55., [PMID:11379881]

Abstract [show]
Based on recent studies of the photoreceptor-specific ABC transporter gene ABCR (ABCA4) in Stargardt disease (STGD1) and other retinal dystrophies, we and others have developed a model in which the severity of retinal disease correlates inversely with residual ABCR activity. This model predicts that patients with late-onset STGDI may retain partial ABCR activity attributable to mild missense alleles. To test this hypothesis, we used late-onset STGDI patients (onset: > or =35 years) to provide an in vivo functional analysis of various combinations of mutant alleles. We sequenced directly the entire coding region of ABCR and detected mutations in 33/50 (66%) disease chromosomes, but surprisingly, 11/33 (33%) were truncating alleles. Importantly, all 22 missense mutations were located outside the known functional domains of ABCR (ATP-binding or transmembrane), whereas in our general cohort of STGDI subjects, alterations occurred with equal frequency across the entire protein. We suggest that these missense mutations in regions of unknown function are milder alleles and more susceptible to modifier effects. Thus, we have corroborated a prediction from the model of ABCR pathogenicity that (1) one mutant ABCR allele is always missense in late-onset STGD1 patients, and (2) the age-of-onset is correlated with the amount of ABCR activity of this allele. In addition, we report three new pseudodominant families that now comprise eight of 178 outbred STGD1 families and suggest a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (approximately 1/22).

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106 351 Table 2 Novel and previously reported polymorphic sites identified in the ABCR gene in late-onset STGD subjects and controls (bold novel polymorphic sites) Exon Nucleotide alteration Predicted AA change STGD1 chromosomes Control chromosomes P value Reference 6 635 GÆA R212H 1/50 Simonelli et al. (2000) 7 IVS6-32 TÆC 4/48 N. F. Shroyer et al. (in preparation) 10 IVS9-14CÆÆÆÆT 22/50 (44%) 18/166 (10.8%) P<0.001 Present study 10 1268AÆG H423R 10/50 (20%) 46/170 (27%) P<0.4 Rivera et al. (2000) 10 1269CÆT H423H 4/50 (8%) 7/170 (4%) P<0.2 Rivera et al. (2000) 10 IVS10+11delG 16/50 (32%) 57/170 (33.5%) P>0.5 Papaioannou et al. (2000) 19 2828 GÆA R943Q 4/50 Allikmets et al. (1997b) 28 4203 CÆA P1401P 7/50 Maugeri et al. (1999) 33 IVS33+48TÆÆÆÆC 22/50 (44%) 48/114 (42%) P<0.5 Present study 39 IVS38-10CÆT 1/48 Maugeri et al. (1999) 40 5603AÆT N1868I 8/48 Stone et al. (1998) 41 5814AÆG L1938L 3/50 N. F. Shroyer et al. (in preparation) 42 IVS41-44CÆA 3/48 N. F. Shroyer et al. (in preparation) 42 IVS41-11GÆA 3/48 Maugeri et al. (1999) 42 5844AÆG P1948P 2/48 Maugeri et al. (1999) 44 IVS43-16GÆA 1/48 N. F. Shroyer et al. (in preparation) 44 6069CÆT I2023I 4/50 Allikmets et al. (1997b) 45 6249CÆT I2083I 4/50 Maugeri et al. (1999) 45 IVS45+7GÆA 5/50 (10%) 9/160 (5.6%) P>0.1 Papaioannou et al. (2000) 49 IVS48-3TÆC 3/50 (6%) 10/170 (5.9%) P>0.9 Maugeri et al. (1999) 49 6764GÆT S2255I 3/50 Allikmets et al. (1997b) 49 IVS49+27GÆC 2/48 Papaioannou et al. (2000) All missense mutations in late-onset STGD1 occur outside known functional regions of ABCR The positions of late-onset associated ABCR missense mutations were placed on the predicted ABCR structure that includes four regions of known function (transmembrane and ATP-binding domains in each of two symmetric halves of the protein). 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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83 Table 4 Polymorphisms in the ABCA4 Gene EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (n p 288) AMD (n p 400) Control (n p 440) 6: 635GrA R212H 8 8 32 This study 7: IVS6-32TrC Unknown 53 115 130 This study 10: 1267ArG H423R 52 79 101 This study 1268CrT H423H 11 17 17 This study 14: IVS14ϩ50TrCa Unknown 22 18 9 This study 19: 2828GrAa R943Q 23 14 10 Allikmets et al. (1997a, 1997b), Maugeri et al. (1999), Papaioannou et al. (2000) 28: 4203CrA P1401P 29 13 20 Maugeri et al. (1999) 33: IVS32-38CrT Unknown 1 4 12 This study 34: IVS33-16delGT Unknown 24 8 12 This study 40: 5603ArT N1868I 37 40 46 Maugeri et al. (1999) 5682GrC L1894L 73 52 91 Maugeri et al. (1999), Papaioannou et al. (2000) 41: 5814ArG L1938L 50 68 70 This study 42: IVS41-11GrA Unknown 46 56 55 Maugeri et al. (1999) 5844ArG P1948P 40 40 39 Maugeri et al. (1999), Papaioannou et al. (2000) 5843CArTG P1948L 5 14 13 Maugeri et al. (1999) 44: IVS43-16GrA Unknown 46 48 55 Papaioannou et al. (2000) 45: IVS45ϩ7GrA Unknown 10 15 11 Papaioannou et al. (2000) 6249CrT I2083I 13 17 27 Allikmets et al. (1997a), Maugeri et al. (1999) 46: 6285TrC D2095D 38 36 33 Maugeri et al. (1999) a 2828GrA and IVS14ϩ50TrC occur on the same haplotype together with 2588GrC. Login to comment
101 Nineteen different alterations were present in 11% of the control alleles and were classified as polymorphisms (table 4); these include five nonconservative amino acid substitutions (R212H, H423R, R943Q, N1868I, and P1948L). 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] ABCR gene analysis in familial exudative age-relat... Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7. Souied EH, Ducroq D, Rozet JM, Gerber S, Perrault I, Munnich A, Coscas G, Soubrane G, Kaplan J
ABCR gene analysis in familial exudative age-related macular degeneration.
Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7., [PMID:10634626]

Abstract [show]
PURPOSE: Identification of genetic factors in the pathogenesis of age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Mutations in the Stargardt disease gene (ABCR) were previously reported in patients with atrophic forms of AMD. The purpose of this study was to analyze familial segregation of ABCR gene mutations in 52 unrelated multiplex cases of exudative AMD. METHODS: A complete ophthalmological examination including visual acuity measurement, fundus examination, and fluorescein angiography (FA) was performed on each exudative AMD patient. The entire coding sequence of the ABCR gene was analyzed using a combination of single-strand conformation polymorphism and confirmatory sequencing of the exons showing an abnormal pattern of migration. RESULTS: Six heterozygous missense changes were identified. A lack of familial segregation was observed in 4 of 6 codon changes (Arg943Gln, Val1433Ile, Pro1948Leu, and Ser2255Ile). Conversely, 2 codon changes cosegregated with the disease in 2 small families: Pro940Arg and Leu1970Phe. CONCLUSIONS: The authors believe that segregation of the ABCR gene mutations with familial cases of AMD has not yet been shown. The analysis of familial segregation allowed the authors to exclude 4 of 6 codon changes as disease-causing mutations. Furthermore, it was shown here that the ABCR gene may be rarely involved in exudative AMD, with at best 2 of 52 familial cases (4%) related to this susceptibility factor.

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8 A lack of familial segregation was observed in 4 of 6 codon changes (Arg943Gln, Val1433Ile, Pro1948Leu, and Ser2255Ile). Login to comment
40 The heterozygous codon changes observed were Pro940Arg, Arg943Gln (2 families), Pro1948Leu (2 families), Leu1970Phe, Val1433Ile, and Ser2255Ile. Login to comment
41 The Arg943Gln, Pro1948Leu, and Ser2255Ile substitutions were observed in the control group: in 3 of 90, 3 of 90, and 1 of 90, respectively. Login to comment
43 No cosegregation of the base substitution with the disease was observed in the families harboring either Arg943Gln, Val1433Ile, Pro1948Leu, or Ser2255Ile changes. Login to comment
53 In these studies, the Arg943Gln and Ser2255Ile codon changes have been reported as polymorphisms. Login to comment
54 Here, the lack of detection of Arg943Gln, Pro1948Leu, and Ser2255Ile in controls was not particularly meaningful and did not permit us to establish statistical significance. Login to comment
63 First, a lack of segregation was observed, for the Arg943Gln, Val1433Ile, Pro1948Leu, and Ser2255Ile changes. Login to comment

[hide] An analysis of ABCR mutations in British patients ... Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9. Papaioannou M, Ocaka L, Bessant D, Lois N, Bird A, Payne A, Bhattacharya S
An analysis of ABCR mutations in British patients with recessive retinal dystrophies.
Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9., [PMID:10634594]

Abstract [show]
PURPOSE: Several reports have shown that mutations in the ABCR gene can lead to Stargardt disease (STGD)/fundus flavimaculatus (FFM), autosomal recessive retinitis pigmentosa (arRP), and autosomal recessive cone-rod dystrophy (arCRD). To assess the involvement of ABCR in these retinal dystrophies, the gene was screened in a panel of 70 patients of British origin. METHODS: Fifty-six patients exhibiting the STGD/FFM phenotype, 6 with arRP, and 8 with arCRD, were screened for mutations in the 50 exons of the ABCR gene by heteroduplex analysis and direct sequencing. Microsatellite marker haplotyping was used to determine ancestry. RESULTS: In the 70 patients analyzed, 31 sequence changes were identified, of which 20 were considered to be novel mutations, in a variety of phenotypes. An identical haplotype was associated with the same pair of in-cis alterations in 5 seemingly unrelated patients and their affected siblings with STGD/FFM. Four of the aforementioned patients were found to carry three alterations in the coding sequence of the ABCR gene, with two of them being in-cis. CONCLUSIONS: These results suggest that ABCR is a relatively polymorphic gene. Because putative mutations have been identified thus far only in 25 of 70 patients, of whom only 8 are compound heterozygotes, a large number of mutations have yet to be ascertained. The disease haplotype seen in the 5 patients carrying the same "complex" allele is consistent with the presence of a common ancestor.

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43 In the family of a STGD/FFM patient, three sequence alterations Cys-54-Tyr, Gly-863-Ala, and Arg-943-Gln in ABCR exons 3, 17, and 19, respectively, were found to be present. Login to comment
44 Both the Gly-863-Ala and Arg-943-Gln substitutions were present in the unaffected mother who had no clinical evidence of the disease at the age of 58 years. Login to comment
46 TABLE 2. List of Polymorphisms Found in 70 Patients of British Origin Nucleotide Change Exon Amino Acid Change No. of Patients (/70) No. of Controls (/96) 1356ϩ11delG 10 intron - 2 NF *G2828A 19 Arg-943-Gln 8 16/176 3815-82G3C 25 intron - 1 NF G5682C 40 Leu-1894-Leu 1 30 C5842T 42 Pro-1948-Leu 4 7 G5844A 42 Pro-1948-Pro 12 22 T5885C 42 Val-1962-Val 9 NF 6006-16G3A 43 intron - 19 NF 6729ϩ21C3T 48 intron - 2 NF 6816ϩ27G3C 49 intron - 4 NF * Independently reported by Allikmets et al.6 NF, not found. Login to comment
49 We therefore assumed that the two sequence changes Gly-863-Ala and Arg-943-Gln were in-cis on the maternally inherited chromosome, comprising a "complex" allele. Login to comment
51 When screening additional patients, we discovered that four more individuals affected with STGD/FFM carried the same two changes in-cis (Gly-863-Ala and Arg-943-Gln). Login to comment
62 The allele in question is the "complex" one carrying two sequence changes, Gly-863-Ala and Arg-943-Gln, in-cis. Login to comment
65 Of the two amino acid alterations in-cis, Gly-863-Ala besides being a putative missense mutation could also affect proper RNA splicing as it occurs at the acceptor splice site of exon 17.13 The second alteration, Arg-943-Gln, has been classified as a "polymorphism. Login to comment
69 Ancestral Haplotype Shared by the 5 Families Carrying the Two Amino Acid Alterations Gly-863-Ala and Arg-943-Gln in-cis Marker Distance Family 1 Family 2 Family 3 Family 4 Family 5 1a 1b 1c 1d 2a 2b 5a 5b D1S198 2 2 2 2 2 2 2 2 2 2 6.2 D1S216 2 2 2 2 2 2 2 2 2 2 10.4 D1S207 3 3 3 3 3 3 - 3 3 3 11.9 D1S2813 1 1 1 1 1 1 1 1 1 1 ABCR gene 2.9 D1S236 1 1 1 1 1 1 1 1 1 1 10.9 D1S248 4 4 4 4 5 5 5 5 2 2 11.8 D1S252 1 1 1 1 1 1 - 1 2 2 9.0 D1S305 1 1 1 1 1 1 2 - 2 2 Column 1 denotes the markers used for haplotyping analysis, and column 2 shows the genetic distance between the respective markers (in cM). Login to comment

[hide] Allelic variation in ABCR associated with Stargard... Nat Genet. 1998 Dec;20(4):328-9. Stone EM, Webster AR, Vandenburgh K, Streb LM, Hockey RR, Lotery AJ, Sheffield VC
Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration.
Nat Genet. 1998 Dec;20(4):328-9., [PMID:9843201]

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23 The 3 common variants (Asn1868Ile, Arg943Gln and Ser2255Ile) were all present in more than 4% of all 3 groups. Login to comment
69 Three non-conservative variants (Asn1868Ile, Arg943Gln and Ser2255Ile) were very common (>4%) in all three groups. 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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110 Alteration AMD STGD1 General population V643G 1/167 (0.6%) 0/98 (0%) 1/80 (1.25%) D846H 0/167 (0%) 1/98 (1%) 1/50 (2%) G863A 1/167 (0.6%) 13/150 (8.7%) 2/220 (0.9%) R943Q 6/127 (4.7%) 4/47 (9.5%) 13/80 (16.25%) S2255I 24/167 (14.4%) 8/98 (8%) 6/58 (10.3%) SCIENCE ⅐ VOL. Login to comment
107 Alteration AMD STGD1 General population V643G 1/167 (0.6%) 0/98 (0%) 1/80 (1.25%) D846H 0/167 (0%) 1/98 (1%) 1/50 (2%) G863A 1/167 (0.6%) 13/150 (8.7%) 2/220 (0.9%) R943Q 6/127 (4.7%) 4/47 (9.5%) 13/80 (16.25%) S2255I 24/167 (14.4%) 8/98 (8%) 6/58 (10.3%) SCIENCE z VOL. 277 z 19 SEPTEMBER 1997 z www.sciencemag.org which map primarily to the highly conserved ATP-binding regions of the ABCR protein, AMD alterations were found outside these domains (Fig. 1). Login to comment

[hide] Evaluation of the common variants of the ABCA4 gen... Int J Mol Med. 2008 Jun;21(6):715-20. Shastry BS
Evaluation of the common variants of the ABCA4 gene in families with Stargardt disease and autosomal recessive retinitis pigmentosa.
Int J Mol Med. 2008 Jun;21(6):715-20., [PMID:18506364]

Abstract [show]
Stargardt disease (STGD) is one of the most common autosomal recessive retinal dystrophies with an estimated incidence of one in 10,000. It affects the central retina (macula). Retinitis pigmentosa (RP) comprises a large and exceptionally heterogeneous group of hereditary disorders of the retina. It is caused by the loss of photoreceptors. The condition is a degenerative disorder characterized by retinal pigment deposits and has an estimated incidence of one in 4,000. Although, to date, 45 known loci have been identified, none of them independently account for a substantial portion of RP. Recently, the photoreceptor cell-specific ATP-binding cassette transporter (ABCA4) gene was found to be mutated in patients with STGD as well as autosomal recessive RP. In order to further understand the contribution of this gene to the susceptibility to STGD and RP, we analyzed three unrelated STGD families and one autosomal recessive RP family specifically for the more common variants (A1038V, G1961E, 2588G-->C, R943Q or 2828G-->A) in the ABCA4 gene. Our analyses employing standard techniques such as polymerase chain reaction, restriction fragment length polymorphism, and direct DNA sequencing of amplified products were able to identify one common variant (R943Q) in all three STGD families but not in the RP family. All three affected STGD individuals, however, were heterozygous for this variation, and this alteration did not segregate with the disease and was also present in the normal controls. Similar analysis of other common variants revealed no pathogenic mutations in the STGD and RP families. It is likely that the variant identified in this study represents a rare polymorphism (non-pathogenic). Although, at present we cannot eliminate the possibility of this gene as a candidate gene, future extensive studies on this as well as other candidate genes may uncover the susceptibility gene for these recessive forms of the disorders in these families.

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8 In order to further understand the contribution of this gene to the susceptibility to STGD and RP, we analyzed three unrelated STGD families and one autosomal recessive RP family specifically for the more common variants (A1038V, G1961E, 2588G&#a1;C, R943Q or 2828G&#a1;A) in the ABCA4 gene. Login to comment
9 Our analyses employing standard techniques such as polymerase chain reaction, restriction fragment length polymorphism, and direct DNA sequencing of amplified products were able to identify one common variant (R943Q) in all three STGD families but not in the RP family. Login to comment
49 To further extend the diagnostic and prognostic value of the molecular genetic study of STGD and to understand the genetic heterogeneity of RP, in this report we analyzed three unrelated STGD families and one AR RP family specifically for the more common variants (A1038V, G1961E, R943Q or 2828G&#a1;A and 2588G&#a1;C) of the ABCA4 gene which when mutated produce a broad spectrum of the retinal phenotypes including RP and age-related macular degeneration (AMD). Login to comment
79 The amplified product was subjected to restriction enzyme digestion with either 10 units of Alu I (2588G&#a1;C mutation in exon 17 of ABCA4 gene creates a site for Alu I), or Bse YI (A1038V mutation in exon 21 destroys a site for Bse YI), or Taq I (G1961E variation in exon 42 in ABCA4 creates a Taq I site), or Msp I (R943Q alteration in exon 19 destroys the Msp I site), or Nla III (Y402H mutation in exon 9 of the CFH gene creates a Nla III site) at 37da;C (Alu I, Bse YI, Msp I, Nla III) and 65da;C (Taq I) for 1 h. Login to comment
83 The finding that the variants A1038V (exon 21), G1961E (exon 42), 2588G&#a1;C (exon 17) and R943Q (exon 19) which is previously known as 2828G&#a1;A (4) are more common INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 21: 715-720, 2008 717 Figure 1. Login to comment
92 The restriction enzyme digestion patterns for R943Q (Msp I) and G1961E (Taq I) changes are shown in Fig. 3A and B respectively. Login to comment
97 This experiment demonstrated that three out of four patients were heterozygous for the R943Q alteration, but this mutation did not segregate in the family (family 1). Login to comment
103 Restriction digestion patterns of PCR-amplified products for R943Q (A) and G1961E (B) variants. Login to comment
104 All three patients (patients II-1 in families 1-3) were heterozygous (lanes 3-8 in A) for the R943Q mutation whereas the affected individual I-3 in family 1 was completely normal (lanes 9-10). Login to comment
125 Our analysis detected only one of the more common variants R943Q (also known as 2828G&#a1;A) located in exon 19 in all three STGD families (but not in RP), and three of the four affected individuals were heterozygous for this mutation. Login to comment
126 The R943Q alteration results in a non-conservative amino acid substitution, and this variation was most often found to be in linkage disequilibrium with presumably a pathogenic variation 2588G&#a1;C in exon 17 in a western European population (4). Login to comment
128 Additionally, as suggested by others, the R943Q variation may not be a pathogenic mutation by itself because it was not segregating in the family (STGD family 1), and the affected individual (I-3) had normal alleles (Fig. 3A, lanes 9-10). Login to comment
135 We also cannot assess the functional consequences of the R943Q alteration in the affected individuals at present because there is no functional test for ABCA4 activity. Login to comment

[hide] Retinoid binding properties of nucleotide binding ... J Biol Chem. 2012 Dec 28;287(53):44097-107. doi: 10.1074/jbc.M112.409623. Epub 2012 Nov 9. Biswas-Fiss EE, Affet S, Ha M, Biswas SB
Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4.
J Biol Chem. 2012 Dec 28;287(53):44097-107. doi: 10.1074/jbc.M112.409623. Epub 2012 Nov 9., [PMID:23144455]

Abstract [show]
The retina-specific ATP binding cassette transporter, ABCA4 protein, is associated with a broad range of inherited macular degenerations, including Stargardt disease, autosomal recessive cone rod dystrophy, and fundus flavimaculatus. In order to understand its role in retinal transport in rod out segment discs, we have investigated the interactions of the soluble domains of ABCA4 with both 11-cis- and all-trans-retinal. Using fluorescence anisotropy-based binding analysis and recombinant polypeptides derived from the amino acid sequences of the four soluble domains of ABCA4, we demonstrated that the nucleotide binding domain 1 (NBD1) specifically bound 11-cis-retinal. Its affinity for all-trans-retinal was markedly reduced. Stargardt disease-associated mutations in this domain resulted in attenuation of 11-cis-retinal binding. Significant differences in 11-cis-retinal binding affinities were observed between NBD1 and other cytoplasmic and lumenal domains of ABCA4. The results suggest a possible role of ABCA4 and, in particular, the NBD1 domain in 11-cis-retinal binding. These results also correlate well with a recent report on the in vivo role of ABCA4 in 11-cis-retinal transport.

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102 Lane 1, WT-NBD1; lane 2, mutant P940R; lane 3, mutant R943Q; lane 4, mutant G863A. Login to comment
171 Error bars, S.D. TABLE 1 Thermodynamic and kinetic parameters of 11-cis-retinal binding and nucleotide hydrolysis for wild-type and mutant NBD1 proteins Parameter Wild type R943Q P940R G863A Enzyme kinetics Vmax (pmol/min/mg) ATP 584 392 129 128 CTP 376 172 84 104 Retinal binding 11-cis-Retinal Kd (M) 8.0 afe; 1.3 afb; 10afa;8 8.0 afe; 2.0 afb; 10afa;6 4.0 afe; 1.4 afb; 10afa;6 c56;1.0 afb; 10afa;5 11-cis-Retinal af9; 1.0 mM AMP-PNP Kd (M) 4.1 afe; 0.6 afb; 10afa;6 NDa ND ND 11-cis-Retinal af9; 1.0 mM ADP Kd (M) 3.6 afe; 0.8 afb; 10afa;7 ND ND ND -Fold inhibition NAb 100 50 NA Disease severity af9;/afa; af9;af9; af9;af9; a ND, not detectable with a ᐵ11-cis-retinalᐶ of c55;1 afb; 10afa;5 M. b NA, not applicable. Login to comment
174 Three ABCA4 mutations associated with Stargardt disease (R943Q, P940R, and G863A) were chosen for analysis in this study. Login to comment
178 We have explored the effects of missense mutations R943Q, P940R, and G863A on 11-cis-retinal interaction with the NBD1. Login to comment
181 Nonlinear regression analysis gave Kd of 8.0 afe; 1.3 afb; 10afa;8 M, 8.0 afe; 2.0 afb; 10afa;6 M, and 4.0 afe; 1.4 afb; 10afa;6 M for the wild type and R943Q and P940R mutations, respectively (Fig. 6 and Table 1). Login to comment
182 As a consequence of Stargardt disease mutations, 100-fold (R943Q) to 50-fold (P940R) decreases in the binding affinity of the NBD1 domain for 11-cis-retinal were observed. Login to comment
197 B, titration of 100 nM 11-cis-retinal with mutant R943Q. Login to comment
215 Three missense mutations in NBD1 were examined in this study, R943Q, P940R, and G863A. Login to comment
220 The mutation P940R seemed to affect 11-cis-retinal interaction the least and led to a b03;50-fold decrease in binding affinity, whereas the R943Q mutation led to a 100-fold decrease FIGURE 7. Login to comment

[hide] ABCA4 mutational spectrum in Mexican patients with... Exp Eye Res. 2013 Apr;109:77-82. doi: 10.1016/j.exer.2013.02.006. Epub 2013 Feb 16. Chacon-Camacho OF, Granillo-Alvarez M, Ayala-Ramirez R, Zenteno JC
ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation.
Exp Eye Res. 2013 Apr;109:77-82. doi: 10.1016/j.exer.2013.02.006. Epub 2013 Feb 16., [PMID:23419329]

Abstract [show]
The aim of this study was to assess the mutational spectrum of the ABCA4 gene in a cohort of patients with Stargardt disease from Mexico, a previously uncharacterized population. Clinical diagnosis in each patient was supported by a complete ophthalmological assessment that included visual acuity measurement, a slit lamp examination, a fundus examination and photography, electroretinography, fluorescein angiography, and computerized visual fields testing. Molecular analysis was performed by PCR amplification and direct nucleotide sequence of the 50 exons of the ABCA4 gene in genomic DNA. A total of 31 unrelated subjects with the disease were enrolled in the study. Molecular analysis in the total group of 62 alleles allowed the identification of 46 mutant ABCA4 alleles carrying 29 different pathogenic disease-associated mutations. Two ABCA4 mutant alleles were detected in 20 of the 31 patients (64.5%), a single disease allele was identified in six (19.4%), and no mutant alleles were detected in five of the cases (16.1%). Most patients with two ABCA4 mutations (11/20, 55%) were compound heterozygotes. Twelve variants were novel ABCA4 mutations. Nucleotide substitutions were the most frequent type of variation, occurring in 26 out of 29 (89.7%) different mutations. The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. The identification of recurrent mutations in our cohort will direct future ABCA4 molecular screening in patients from this ethnic group.

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100 Allele 1 Allele 2 Genotype Exon Nucleotide change Polypeptide change Exon Nucleotide change Polypeptide change Familial case # 1 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 2 e NI e e NI e e 3 6 c.634C>T p.R212C (D) 38 c.5318C>T p.A1773V (D) Compound heterozygous 4 23 c.3386G>T p.R1129L (D) 28 c.4139C>T p.P1380L (D) Compound heterozygous 5 e NI e e NI e e 6 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 7 e NI e e NI e e 8 16 c.2453G>A p.G818E (D) 28 c.4249_4251 delTTC p.F1417del (D; N) Compound heterozygous 9 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous Sporadic case # 1 8 c.868C>T p.R290W (D) e IVS8&#fe;1G>A Splicing (D; N) Compound heterozygous 2 38 c.5318C>T p.A1773V (D) - NI - Heterozygous 3 20 c.3041T>G p.L1014R (D) 1; 49 c.52C>T; c.6764G>T p.R18W (D); p.S2255I (B) Compound heterozygous 4 13; 19 c.1804C>T; c.2828G>A p.R602W (D); p.R943Q (U) 16 c.2453G>A p.G818E (D) Compound heterozygous 5 38 c.5324T>A p. I1775N (D; N) 38 c.5324T>A p.I1775N (D; N) Homozygous 6 e NI e e NI e e 7 49 c.6764G>T p.S2255I (B) 49 c.6764 G>T p.S2255I (B) Homozygous 8 19; 40 c.2828 G>A; c.5503A>T p.R943Q (U); p.N1868I (U) 3 c.265G>T p.E89* (D; N) Compound heterozygous 9 38 c.5335T>C p.Y1779H (D;N) 38 c.5335T>C p.Y1779H (D;N) Homozygous 10 16 c.2453G>A p.G818E (D) 16 c.2453G>A p.G818E (D) Homozygous 11 6 c.723A>T p.E241D (D;N) 36 c.5114G>A p.R1705Q (D) Compound heterozygous 12 2 c.71G>A (D) p.R24H e NI e Heterozygous 13 30 c.4537_4538insC p.Q1513Pfs*41 (D; N) e NI e Heterozygous 14 32 c.4667G>C p.R1556T (D; N) 32 c.4667G>C p.R1556T (D; N) Homozygous 15 45 c.6221G>T p.G2074V (D; N) 16 c.2453G>A p.G818E (D) Compound heterozygous 16 16; 41 c.2453G>A; c.5824G>C p. G818E (D); p. E1942Q (B;N) 46 c.6384A>G p.H2128R (D) Compound heterozygous 17 16 c.2453G>A p. G818E (D) e NI e Heterozygous 18 32 c.4653G>A p. W1551* (D; N) e NI e Heterozygous 19 23 c.3386G>T p. R1129L (D) e NI e Heterozygous 20 36 c.5045_5059del GTTGCCATCTGCGTG p.V1682_ V1686del (D; N) 29; 49 c.4328G>A; c.6764G>T p.R1443H (D); p.S2255I (B) Compound heterozygous 21 19 c.2894A>G p.N965S (D) 19 c.2894A>G p.N965S (D) Homozygous 22 e NI e e NI e e STGD accounts for approximately 7% of all retinal dystrophies; it is one of the most common genetic forms of juvenile or early adult onset macular degeneration. Login to comment
119 ABCA4 Exon # Nucleotide change Predicted protein effect Number of alleles Population genotypic frequency in EVS Population allelic frequency in EVS (%) 1 c.52C>T p.R18W 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 2 c.71G>A p.R24H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 3 c.265G>T p.E89* (N) 1 NR NR 6 c.634C>T p.R212C 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 6 c.723A>T p.E241D (N) 1 NR NR 8 c.868C>T p.R290W 1 NR NR IVS8 IVS8 &#fe; 1G>A Splicing mutation (N) 1 NR NR 13 c.1804C>T p.R602W 1 NR NR 16 c.2453G>A p.G818E 7 NR NR 19 c.2828G>A p.R943Q 2 AA &#bc; 8/AG &#bc; 400/GG &#bc; 6095 A &#bc; 3.199/G &#bc; 96.801 19 c.2894A>G p.N965S 2 GG &#bc; 0/GA &#bc; 1/AA &#bc; 6502 G &#bc; 0.008/A &#bc; 99.992 20 c.3041T>G p.L1014R 1 NR NR 23 c.3386G>T p.R1129L 2 NR NR 28 c.4139C>T p.P1380L 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 28 c.4249_4251del TTC p.F1417del (N) 1 NR NR 29 c.4328G>A p.R1443H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 30 c.4537_4538insC p.Q1513Pfs*41 (N) 1 NR NR 32 c.4653G>A p.W1551* (N) 1 NR NR 32 c.4667G>C p.R1556T (N) 2 NR NR 36 c.5044_5058del GTTGCCATCTGCGTG p.V1682_V1686del (N) 1 NR NR 36 c.5114G>A p.R1705Q 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 38 c.5318C>T p.A1773V 8 NR NR 38 c.5324T>A p.I1775N (N) 2 NR NR 38 c.5335T>C p.Y1779H (N) 2 NR NR 40 c.5503A>T p.N1868I 1 TT &#bc; 16/TA &#bc; 589/AA &#bc; 5898 T &#bc; 4.775/A &#bc; 95.225 41 c.5824G>C p.E1942Q (N) 1 NR NR 45 c.6221G>T p.G2074V (N) 1 NR NR 46 c.6384A>G p.H2128R 1 NR NR 49 c.6764G>T p.S2255I 4 TT &#bc; 516/TG &#bc; 1473/GG &#bc; 4514 T &#bc; 19.26/G &#bc; 80.74 gold standard for ABCA4 mutational screening. Login to comment
138 It is important to make note that three of the variants identified in this work, p.R943Q, p.N1868I, and p.S2255I have an allele frequency in the NHLBI Exome Sequencing Project of 3.2%, 4.8%, and 19% respectively, and thus they are most probably non-pathogenic variants. Login to comment
139 However, with the exception of sporadic case #7 who was homozygous for p.S2255I (sporadic case #7 in Table 1), all remaining 4 patients carrying one of such mutations also carry two additional deleterious ABCA4 mutations (sporadic cases #4, #3, and #20 in Table 1) or a null allele (p.E89*) combined with p.R943Q and p.N1868I (sporadic case #8). Login to comment
141 Moreover, in vitro studies have shown that the ATPase activity of the p.R943Q protein function was reduced about 40% with respect to wild type ABCA4 (Su&#e1;rez et al., 2002) and carriers of p.N1868I variant exhibit a more than twofold risk of developing STGD than those carrying the normal homozygous variant (Aguirre-Lamban et al., 2011). Login to comment
142 Thus, despite its prevalence in general population, the role of the p.R943Q and N1868I ABCA4 mutations in STGD disease is controversial. Login to comment

[hide] A longitudinal study of stargardt disease: clinica... Am J Ophthalmol. 2013 Jun;155(6):1075-1088.e13. doi: 10.1016/j.ajo.2013.01.018. Epub 2013 Mar 15. Fujinami K, Lois N, Davidson AE, Mackay DS, Hogg CR, Stone EM, Tsunoda K, Tsubota K, Bunce C, Robson AG, Moore AT, Webster AR, Holder GE, Michaelides M
A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations.
Am J Ophthalmol. 2013 Jun;155(6):1075-1088.e13. doi: 10.1016/j.ajo.2013.01.018. Epub 2013 Mar 15., [PMID:23499370]

Abstract [show]
PURPOSE: To investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype. DESIGN: Cohort study of 59 patients. METHODS: Clinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3 ms for the 30 Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken. RESULTS: The mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients. CONCLUSIONS: All patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions.

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89 Clinical Data and Molecular Genetic Status of 59 Patients With Stargardt Disease Pt Onset (y) Age (y) logMAR VA Variants Identifieda BL FU BL FU 1 16 17 26 0.0/1.0 0.0/0.48 c.768G>T / p.Gly863Ala / p.Arg943Gln 2 15 17 25 0.78/0.78 1.0/1.0 p. Arg1443His 3 11 18 27 0.78/1.0 1.0/1.0 p.Trp439* / p.Gly863Ala / p.Leu1970Phe 4 19 21 32 0.78/0.78 1.0/1.0 p.Leu2027Phe 5 10 22 30 0.48/0.48 1.0/0.78 p.Gly863Ala / p.Arg943Gln / c.5461-10 T>C 6 18 26 37 0.78/1.0 1.0/1.0 p.Pro1380Phe 7 25 28 40 0.78/1.0 1.3/0.78 ND 8 24 29 38 1.0/0.78 1.0/1.0 p.Phe418Ser / p.Leu2027Phe 9 24 31 44 1.0/1.0 1.3/1.0 c.4253&#fe;5 G>T / p.Gly1507Arg 10 26 32 44 0.78/0.78 1.0/1.0 p.Cys1490Tyr / p.Arg2030Gln 11 31 34 46 0.18/0.3 0.6/0.7 ND 12 17 35 47 1.0/1.0 1.0/1.0 p.Asn96His 13 23 35 45 1.0/0.3 1.0/0.48 p.Gly1513Profs*1554 14 33 37 48 0.18/1.48 1.0/1.3 ND 15 38 40 51 0.18/0.78 1.0/1.0 p.Arg2107His 16 42 43 53 0.0/0.0 1.0/1.0 ND 17 22 48 59 1.0/1.0 1.0/1.0 p.Cys54Tyr 18 20 49 59 1.0/0.6 1.0/1.0 p.Pro1380Leu / p.Gly1961Glu 19 35 50 61 1.0/0.3 1.0/1.0 p.Arg1108Cys 20 25 56 67 1.3/0.18 1.0/1.0 p.Trp439* / p.Gly863Ala 21 48 59 71 1.0/0.78 1.0/1.0 p. Ile156 Val / p. Cys1455Arg / p. Phe1839Ser 22 21 22 31 0.3/1.0 1.0/1.0 p.Arg2107His 23 21 23 33 1.0/1.0 1.0/1.0 p.Gly863Ala 24 48 64 73 0.0/1.0 0.18/3.0 p.Tyr1652* 25 17 19 29 0.78/0.3 1.0/1.0 c.5461-10 T>C 26 17 21 33 1.0/0.78 1.0/1.0 ND 27 27 53 66 1.78/1.78 1.3/1.0 p.Ser1071Cysfs*1084 28 5 14 21 0.78/0.78 1.0/1.0 p.Arg408* / p.Val675lle 29 9 15 27 1.08/1.08 1.0/1.0 p.Cys2150Tyr 30 14 24 32 1.0/0.78 1.0/1.0 ND 31 18 28 39 1.0/1.0 1.0/1.0 p.Gly863Ala / p.Arg1108Cys / p.Arg943Gln 32 14 29 37 1.0/1.0 1.0/1.0 p.Arg653Cys / p.Arg2030Gln 33 19 29 40 1.0/1.0 1.0/1.08 ND 34 34 40 49 0.3/0.48 1.0/1.0 p.Gly863Ala / p.Glu1087Lys 35 25 43 54 1.0/1.0 1.0/1.0 p.Cys54Tyr / p.Gly863Ala 36 38 60 69 1.0/1.0 1.3/1.08 p.Val931Met / c.5461-10 T>C 37 10 11 20 1.0/0.78 1.3/1.3 p.Pro1380Leu 38 10 15 23 1.0/1.0 1.3/1.3 p.Ser1071Cysfs*1084 / p.Pro1380Leu 39 24 25 38 1.56/0.3 2.0/2.0 c.5461-10 T>C / c.5714&#fe;5 G>A 40 18 26 36 1.3/1.3 2.0/1.3 ND 41 32 33 45 0.48/0.48 1.0/1.0 ND 42 32 35 46 1.3/0.0 3.0/1.0 p.Cys54Tyr 43 30 35 45 0.48/0.48 2.0/1.3 ND 44 15 41 49 1.3/1.3 2.0/1.3 p.Asn965Ser 45 8 8 20 0.78/0.78 1.0/1.0 p.Thr1019Met 46 10 11 23 1.0/1.0 1.0/1.0 p.Thr1019Met 47 8 12 24 2.0/1.56 1.78/1.48 p.Cys2150Tyr 48 17 18 26 1.0/0.78 1.3/1.0 c.5461-10 T>C / p.Leu2027Phe 49 8 21 33 1.3/1.3 2.0/2.0 p.Asp574Aspfs*582 50 8 27 39 2.0/1.56 1.78/1.48 c.5461-10 T>C 51 24 31 43 1.18/1.18 1.08/1.3 p.Arg1640Trp / p.Leu2027Phe Continued on next page respective electrophysiologic traces appear in Figure 2. Login to comment
179 All 3 unrelated patients (1, 5, and 31) harboring p.Arg943Gln also had p.Gly863Ala, suggesting linkage disequilibrium of these 2 substitutions, with none of these subjects having clinically significant ERG deterioration. Login to comment
209 Co-inheritance of p.Arg943Gln and p.Gly863Ala has been previously reported,44,45 with p.Arg943Gln thought to be a benign polymorphism29,45 and p.Gly863Ala believed to be associated with milder phenotypes,42,45 although there has been a single report of a severe phenotype associated with p.Gly863Ala in the homozygous configuration.44 Only 2 out of 8 patients harboring p.Gly863Ala in the present series had evidence of ERG progression, suggesting this variant is indeed likely to be associated with milder disease. Login to comment

[hide] Characterization of stargardt disease using polari... Invest Ophthalmol Vis Sci. 2013 Sep 27;54(9):6416-25. doi: 10.1167/iovs.12-11550. Ritter M, Zotter S, Schmidt WM, Bittner RE, Deak GG, Pircher M, Sacu S, Hitzenberger CK, Schmidt-Erfurth UM
Characterization of stargardt disease using polarization-sensitive optical coherence tomography and fundus autofluorescence imaging.
Invest Ophthalmol Vis Sci. 2013 Sep 27;54(9):6416-25. doi: 10.1167/iovs.12-11550., [PMID:23882696]

Abstract [show]
PURPOSE: To identify disease-specific changes in Stargardt disease (STGD) based on imaging with polarization-sensitive spectral-domain optical coherence tomography (PS-OCT) and to compare structural changes with those visible on blue light fundus autofluorescence (FAF) imaging. METHODS: Twenty-eight eyes of 14 patients diagnosed with STGD were imaged using a novel high-speed, large-field PS-OCT system and FAF (excitation 488 nm, emission > 500 nm). The ophthalmoscopic phenotype was classified into three groups. ABCA4 mutation testing detected 15 STGD alleles, six of which harbor novel mutations. RESULTS: STGD phenotype 1 (12 eyes) showed sharply delineated areas of absent RPE signal on RPE segmentation B-scans of PS-OCT correlating with areas of hypofluorescence on FAF. Adjacent areas of irregular fluorescence correlated with an irregular RPE segmentation line with absence of overlaying photoreceptor layers. Eyes characterized on OCT by a gap in the subfoveal outer segment layer (foveal cavitation) showed a normal RPE segmentation line on PS-OCT. Hyperfluorescent flecks on FAF in phenotype 2 STGD (8 eyes) were identified as clusters of depolarizing material at the level of the RPE. Distribution of flecks could be depicted on RPE elevation maps. An increased amount of depolarizing material in the choroid was characteristic for STGD Phenotype 3 (8 eyes). CONCLUSIONS: PS-OCT together with FAF identified characteristic patterns of changes in different stages of the disease. PS-OCT is a promising new tool for diagnosis and evaluation of future treatment modalities in STGD.

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111 [2588G>C; 2828G>A] (p.[Gly863Ala; Arg943Gln]) and a, so far unknown, missense mutation in exon 22, c.3266C>T (p.Thr1089Ile), which affects a highly conserved threonine residue within the transmembrane helix and is predicted to be deleterious. Login to comment

[hide] Common synonymous variants in ABCA4 are protective... BMC Ophthalmol. 2015 Mar 6;15:18. doi: 10.1186/s12886-015-0008-0. Grassmann F, Bergholz R, Mandl J, Jagle H, Ruether K, Weber BH
Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy).
BMC Ophthalmol. 2015 Mar 6;15:18. doi: 10.1186/s12886-015-0008-0., [PMID:25884411]

Abstract [show]
BACKGROUND: Chloroquine (CQ) and hydroxychloroquine (HCQ) are used to treat auto-immune related diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Both drugs however can cause retinal toxicity eventually leading to irreversible maculopathy and retinopathy. Established risk factors are duration and dosage of treatment while the involvement of genetic factors contributing to toxic maculopathy is largely unclear. To address the latter issue, this study aimed to expand on earlier efforts by (1) evaluating risk-altering variants known to be associated with age-related macular degeneration (AMD), a frequent maculopathy in individuals over 55 years of age, and (2) determining the contribution of genetic variants in the coding sequence of the ABCA4 gene. METHODS: The ABCA4 gene was analyzed by deep sequencing technology using a personal genome machine (Ion Torrent) with 200 bp read length. Assessment of AMD variants was done by restriction enzyme digestion of PCR products and TaqMan SNP genotyping. Effect sizes, p-values and confidence intervals of common variants were evaluated by logistic regression (Firth's bias corrected). To account for multiple testing, p-values were adjusted according to the false discovery rate. RESULTS: We found no effects of known AMD-associated variants on the risk of toxic maculopathy. In contrast, we report a statistically significant association of common variants in the ABCA4 gene with retinal disease, assessed by a score-based variance-component test (PSKAT = 0.0055). This association remained significant after adjustment for environmental factors like age and duration of medication and was driven by three common variants in ABCA4 (c.5682G > C, c.5814A > G, c.5844A > G), all conferring a reduced risk for toxic maculopathy. CONCLUSIONS: Our findings demonstrate that minor alleles of common genetic variants in ABCA4 significantly reduce susceptibility to develop toxic maculopathy under CQ treatment. A refined risk profile based on genetic and environmental factors may have implications for revised recommendations in CQ as well as HCQ treatment.

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95 Table 2 Genetic variants identified in ABCA4 sequence analysis in CQ-treated patients with (cases) and without (controls) toxic maculopathy Frequency in Variant (NM_000350.2) Amino acid exchange (NP_000341.2) Cases Controls EURߤ Raw p-value FDR# c.324G > A M114I 0.00 0.04 - - - c.635G > A R212H 0.06 0.08 0.06 - - c.1268A > G* H423R 0.29 0.23 0.30 0.58783 0.58783 c.1269C > T H423H 0.13 0.04 0.07 - - c.1622T > C L541P 0.02 0.00 - - - c.2588G > C G863A 0.00 0.04 0.00 - - c.2828G > A R943Q 0.04 0.12 0.04 - - c.3113C > T A1038V 0.02 0.00 0.00 - - c.4203C > A P1401P 0.00 0.04 - - - c.4297G > A V1433I 0.00 0.04 0.00 - - c.5603A > T N1868I 0.06 0.08 0.07 - - c.5682G > C* L1894L 0.13 0.38 0.26 0.02292 0.030 c.5814A > G* L1938L 0.06 0.31 0.18 0.00722 0.014 c.5843C > T P1948L 0.04 0.08 0.04 - - c.5844A > G* P1948P 0.06 0.31 0.19 0.00722 0.014 c.6069T > C I2023I 0.04 0.08 0.06 - c.6148G > C V2050L 0.02 0.00 0.00 - - c.6249C > T I2083I 0.04 0.08 0.05 - - c.6282 + 7G > A - 0.04 0.08 0.05 - - c.6285T > C D2095D 0.08 0.15 0.10 - - c.6357A > G E2119E 0.02 0.00 - - - c.6730-3T > C - 0.02 0.12 0.02 - - c.6764G > T S2255I 0.02 0.12 0.02 - - *Common variants (combined frequency in cases and controls > 11.6%). Login to comment