ABCMdb

ABCA4 p.His423Arg

ClinVar:	c.1269C>T , p.His423= N , Benign c.1268A>G , p.His423Arg N , Benign/Likely benign, not provided c.1268A>C , p.His423Pro ? , not provided
Predicted by SNAP2:	A: N (53%), C: N (53%), D: D (71%), E: N (57%), F: N (61%), G: D (53%), I: N (61%), K: D (53%), L: N (61%), M: N (66%), N: N (61%), P: D (59%), Q: N (66%), R: N (72%), S: N (61%), T: N (72%), V: N (66%), W: D (59%), Y: N (57%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] 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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12 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 IVS10ϩ5 delG). Login to comment
75 Once this variant was compared to cis-acting polymorphisms, statistical analyses demonstrated significant differences among p.Arg1129Leu and the p.His423Arg and IVS33ϩ48CϾT variants: 94.1% of the p.Arg1129Leu patients also had the p.His423Arg change (P ϭ Ͻ0.001), and 100% of them also carried the IVS33ϩ48CϾT polymorphism (P ϭ 0.003) (Table 3). Login to comment
76 In contrast, the p.Pro1401Pro, p.Asn1868Ile, p.Leu1894Leu, and p.Leu1938Leu variants were less frequently detected among the p.Arg1129Leu patients (Table 3). Login to comment
77 Despite this, p.His423Arg, IVS33ϩ48CϾT, p.Pro1401Pro, p.Leu1894Leu, and p.Leu1938Leu polymorphisms were detected in similar frequencies between p.Arg1129Leu patients and the control population, since no significant differences existed (P ϭ 0.108, 0.542, 0.605, 0.130, and 0.394 respectively). Login to comment
78 p.Gly1961Glu The p.Gly1961Glu mutation was the second most frequent missense variant, with a frequency of 14.1% (Table 1). 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
87 The p.Asn1868Ile variant was found in higher proportion in patients than in control individuals (P ϭ 0.049) (Table 2) and was not present in the 82% of the carrier patients of the p.Gly1961Glu mutation (P ϭ 0.013) (Table 3). Login to comment
93 This variant was significantly associated with p.His423Arg (P ϭ 0.014), p.Asn1868Ile (P Ͻ 0.001), and p.Leu1894Leu (P ϭ 0.016), as 100% of the patients carried both the mutation and these polymorphisms (Table 3). Login to comment
94 p.Arg212H is p.Pro327Pro p.H is423Arg p.H is423H is IVS10+5delG p.Arg602Trp p.Arg943G ln c.3211insG T p.Arg1129Leu p.Pro1401Pro IVS33+48C >Tp.Leu1894Leu p-Leu1938Leu p.Pro1948Leu p.Pro1948Pro p.G ly1961G lup.Leu2060Argp.Asp2095Asp IVS48+21C >T - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - p.Asn1868Ile p.Ile2023Ile p.Ile2083Ile p.Ser2255Ile PATIENTSCONTROLS FIGURE 1. Login to comment
98 However, p.His423Arg was less frequently detected among patients harboring p.Leu2060Arg, since the frequency of this occurrence was 14.3% (P ϭ 0.05) (Table 3). Login to comment
101 Polymorphisms and Risk Carriers of the p.His423Arg and IVS10ϩ5 delG variants have a diminished risk of disease compared to normal homozygous variant (OR: AGϩGG ϭ 0.46; 95% CI, 0.25-0.86; P ϭ 0.015; and OR: N/D ϩ DD ϭ 0.45; 95% CI, 0.25-0.80; P ϭ 0.007, respectively; Table 4). Login to comment
108 The p.His423Arg and IVS10ϩ5 delG polymorphisms show a protective effect of the disease (OR: AGϩGG ϭ 0.46; 95% CI, 0.25-0.86; P ϭ 0.015, and OR: N/D ϩ DD ϭ 0.45; 95% CI, 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
110 Polymorphisms and Risk of Stargardt Disease Polymorphism Genotype Cases (n ‫؍‬ 128) N Controls (n ‫؍‬ 84) N OR 95% CI P p.His423Arg AA 60 30 1 (reference) AGϩGG 68 54 0.464 0.250-0.863 0.015 IVS10ϩ5 delG Normal 92 45 1 (reference) N/DϩD/D 36 39 0.452 0.254-0.804 0.007 p.Asn1868Ile AA 101 75 1 (reference) ATϩTT 27 9 2.23 0.990-5.015 0.05 0.25-0.80; P ϭ 0.007, respectively). Login to comment
114 This is the case of the p.His423Arg polymorphism and the p.Gly1961Glu and p.Leu2060Arg mutations (P ϭ 0.023; Table 3); in other cases, however, the same polymorphism was found in association with the pArg1129Leu and c.3211insGT mutations. Login to comment
118 The p.Gly1961Glu variant was found in 18 (out of 128) STGD patients and was considered a moderate allele.9 However, there is no linkage disequilibrium, since five out of 18 STGD patients did not carry the IVS48ϩ21CϾT polymorphism. Login to comment
120 In a Danish population, both ABCA4 gene variants were found, though no possible association was analyzed.18 However, in a German population, 18 individuals were found to have the IVS48ϩ21CϾT polymorphism, of whom 17 had the p.Gly1961Glu mutation.15 As a contrast, p.Asn1868Ile and p.His423Arg are negatively associated with the p.Gly1961Glu mutation. Login to comment
121 p.Asn1868Ile appears at a higher frequency in patients than in controls (P ϭ 0.049), although previous studies have found the variant to occur in higher, albeit insignificant, frequency among the control population.19 The IVS10ϩ5delG polymorphism was first described in 2001 by Webster et al.18 in a study on a Danish population. Login to comment
125 This mutation is hardly present at all in other populations.20 Appearing in 34 of 128 patients, the mutation is associated with both p.His423Arg and IVS33ϩ48CϾT polymorphisms (P ϭ 0.001 and 0.003, respectively). Login to comment
128 These facts suggest that the variants do not contribute to the disease and that the p.Arg1129Leu mutation is more recent than these polymorphisms. 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
148 In conclusion, the p.His423Arg and IVS10ϩ5delG polymorphisms have a protective effect, whereas the p.Asn1868Ile polymorphism is a risk factor for disease. Login to comment
134 This is the case of the p.His423Arg polymorphism and the p.Gly1961Glu and p.Leu2060Arg mutations (P afd; 0.023; Table 3); in other cases, however, the same polymorphism was found in association with the pArg1129Leu and c.3211insGT mutations. Login to comment
140 In a Danish population, both ABCA4 gene variants were found, though no possible association was analyzed.18 However, in a German population, 18 individuals were found to have the IVS48af9;21Cb0e;T polymorphism, of whom 17 had the p.Gly1961Glu mutation.15 As a contrast, p.Asn1868Ile and p.His423Arg are negatively associated with the p.Gly1961Glu mutation. Login to comment
145 This mutation is hardly present at all in other populations.20 Appearing in 34 of 128 patients, the mutation is associated with both p.His423Arg and IVS33af9;48Cb0e;T polymorphisms (P afd; 0.001 and 0.003, respectively). Login to comment
168 In conclusion, the p.His423Arg and IVS10af9;5delG polymorphisms have a protective effect, whereas the p.Asn1868Ile polymorphism is a risk factor for disease. Login to comment

[hide] Genetic association study of age-related macular d... Acta Ophthalmol. 2011 Feb;89(1):e12-22. doi: 10.1111/j.1755-3768.2010.02040.x. Epub 2010 Nov 25. Brion M, Sanchez-Salorio M, Corton M, de la Fuente M, Pazos B, Othman M, Swaroop A, Abecasis G, Sobrino B, Carracedo A
Genetic association study of age-related macular degeneration in the Spanish population.
Acta Ophthalmol. 2011 Feb;89(1):e12-22. doi: 10.1111/j.1755-3768.2010.02040.x. Epub 2010 Nov 25., [PMID:21106043]

Abstract [show]
PURPOSE: To investigate new genetic risk factors and replicate reported associations with advanced age-related macular degeneration (AMD) in a prospective case-control study developed with a Spanish cohort. METHODS: Three hundred and fifty-three unrelated patients with advanced AMD (225 with atrophic AMD, 57 with neovascular AMD, and 71 with mixed AMD) and 282 age-matched controls were included. Functional and tagging SNPs in 55 candidate genes were genotyped using the SNPlex genotyping system. Single SNP and haplotype association analysis were performed to determine possible genetic associations; interaction effects between SNPs were also investigated. RESULTS: In agreement with previous reports, ARMS2 and CFH genes were strongly associated with AMD in the studied Spanish population. Moreover, both loci influenced risk independently giving support to different pathways implicated in AMD pathogenesis. No evidence for association of advanced AMD with other previous reported susceptibility genes, such as CST3, CX3CR1, FBLN5, HMCN1, PON1, SOD2, TLR4, VEGF and VLDLR, was detected. However, two additional genes appear to be candidate markers for the development of advanced AMD. A variant located at the 3' UTR of the FGF2 gene (rs6820411) was highly associated with atrophic AMD, and the functional SNP rs3112831 at ABCA4 showed a marginal association with the disease. CONCLUSION: We performed a large gene association study in advanced AMD in a Spanish population. Our findings show that CFH and ARMS2 genes seem to be the principal risk loci contributing independently to AMD in our cohort. We report new significant associations that could also influence the development of advanced AMD. These findings should be confirmed in further studies with larger cohorts.

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178 We observed a marginal allelic association with the missense H423R variant (rs3112831) with advanced AMD. 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] 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] Electroretinographic findings in patients with Sta... Retina. 2004 Dec;24(6):920-8. Oh KT, Weleber RG, Stone EM, Oh DM, Rosenow J, Billingslea AM
Electroretinographic findings in patients with Stargardt disease and fundus flavimaculatus.
Retina. 2004 Dec;24(6):920-8., [PMID:15579991]

Abstract [show]
PURPOSE: To characterize the clinical and electroretinogram (ERG) features of our cohort of patients with Stargardt disease (STGD) exhibiting coding sequence variations in the ABCA4 gene. METHODS: Review of 76 patients with the clinical diagnosis of Stargardt disease/fundus flavimaculatus (STGD/FF) from the University of Iowa Department of Ophthalmology and Visual Sciences (41 patients) and the Casey Eye Institute (35 patients). Clinical examination, Goldmann perimetry, and electroretinography were performed on all 76 patients. Patients were divided into three groups on the basis of their funduscopic and electroretinographic features: (1) a normal ERG by the standards of the laboratory; (2) minimal rod or cone abnormalities; (3) severe ERG dysfunction. The latter category was further subdivided on the basis of a cone-dominated loss of function (C > R or "cone-rod dystrophy") or diffuse depression of rods and cones (C = R). Mutational analysis of the coding sequence of the ABCA4 gene was performed by single strand conformation polymorphism analysis followed by automated DNA sequencing. Each electroretinographic group was analyzed for the presence of disease causing changes using exact tests of binomial proportions corrected for multiple comparisons by Bonferroni method. Quantitative polymerase chain reaction (QPCR) was performed on patients who were homozygous for disease causing changes in the ABCA4 gene to rule out the possibility of deletions. RESULTS: Overall, 56 of 76 patients (and 77 of 152 alleles) exhibited coding sequence variations that were compatible with high-penetrance disease-causing mutations. The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. However, a significantly greater fraction of patients with normal ERG studies failed to exhibit detectable disease-causing coding sequence variations in the ABCA4 gene identified on either allele (P = 0.0006). CONCLUSION: STGD/FF patients in our cohort exhibit a wide range of electroretinographic abnormalities, some of which are more prevalent than previously suspected. No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. The presence of electrophysiologic dysfunction is not uncommon in our cohort of patients with STGD. Thus, the ERG provides clinically important information of retinal function for STGD/FF and, as such, is still indicated as part of the evaluation of these patients.

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9 The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Login to comment
10 Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. Login to comment
13 No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. Login to comment
165 In fact, the six most common HPRDCV, with the exception of His423Arg, (frameshift changes, Ala1038Val, Pro1380Leu, Arg1108Cys, Leu2027Phe) were observed with all three ERG classes: severe ERG derangements, mild ERG derangements, and normal ERG studies. Login to comment
170 The common Gly1961Glu sequence variation was notably absent from patients with severe ERG findings but was present in two patients with normal ERGs and one patient with mild ERG derangements, suggesting that this is either a marker polymorphism for a heretofore unidentified mutation or itself a mild disease-causing allele.34 However, His423Arg was only seen in patients with electrophysiologic derangements, suggesting that it may have a marked effect on gene function or lead to greater loss of photoreceptor function. Login to comment
172 The fifth patient, who also manifested a severely affected ERG, was heterozygous for His423Arg with the other allele bearing a Leu1014Arg change. 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] 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
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] Detailed analysis of allelic variation in the ABCA... Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2868-75. Schmidt S, Postel EA, Agarwal A, Allen IC Jr, Walters SN, De la Paz MA, Scott WK, Haines JL, Pericak-Vance MA, Gilbert JR
Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.
Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2868-75., [PMID:12824224]

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

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123 Polymorphisms and Rare Sequence Variants in Exons of the ABCA4 Gene Exon Nucleotide Change Effect Allele Frequency* P† P§ Referenceሻ Independent ARM (n ‫؍‬ 140) All ARM (n ‫؍‬ 330) Control Subjects (n ‫؍‬ 118) 6 589G3C Asp197Asn 0.000 0.000 0.009 0.46 0.12 - 6 635G3A Arg212His 0.030 0.026 0.000 0.13 0.11 W, R 10 1268A3G His423Arg 0.394 0.371 0.427 0.62‡ 0.34 W, R 10 1269C3T His423His(syn) 0.033 0.039 0.031 1.0 0.74 W 18 2701A3G Thr901Ala 0.000 0.003 0.000 NA 0.58 W, R 23 3495C3T Asn1165Asn(syn) 0.000 0.003 0.000 NA 0.75 - 30 4469G3A Cys1490Tyr 0.007 0.003 0.000 1.0 0.59 W 37 5206T3C Ser1736Pro 0.009 0.008 0.000 1.0 0.44 W 40 5603T3A Asn1868Ile 0.100 0.102 0.054 0.29 0.18 W 40 5682G3C Leu1894Leu(syn) 0.293 0.272 0.298 1.0 0.64 W 41 5814A3G Leu1938Leu(syn) 0.160 0.169 0.218 0.33 0.38 W 42 5843C3T Pro1948Leu 0.052 0.038 0.054 1.0 0.50 W 42 5844A3G Pro1948Pro(syn) 0.199 0.192 0.205 1.0 0.77 W 44 6069C3T Ile2023Ile(syn) 0.040 0.050 0.044 1.0 0.82 W 44 6079C3T Leu2027Phe 0.000 0.000 0.009 0.48 0.13 W * Actual n (number of chromosomes) varies, as frequencies were calculated relative to nonmissing data only. 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] 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

[hide] Analysis of the ABCR (ABCA4) gene in 4-aminoquinol... Am J Ophthalmol. 2001 Jun;131(6):761-6. Shroyer NF, Lewis RA, Lupski JR
Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease?
Am J Ophthalmol. 2001 Jun;131(6):761-6., [PMID:11384574]

Abstract [show]
PURPOSE: To determine if mutations in ABCR (ABCA4) are associated with chloroquine/hydroxychloroquine retinopathy. METHODS: DNA from eight patients with chloroquine or hydroxychloroquine retinopathy was studied. Controls were 80 individuals over age 65 years with normal retinal examinations. Ophthalmoscopy, color vision testing, visual fields, retinal photography, and fluorescein angiography were performed on the eight patients. Direct DNA sequencing of the exons and flanking intronic regions of the ABCR gene was completed for all patients. RESULTS: Clinical evaluation confirmed the diagnosis of chloroquine/hydroxychloroquine retinopathy and excluded Stargardt disease in each patient. Two patients had heterozygous ABCR missense mutations previously associated with Stargardt disease. None of the controls had these missense mutations. Three other patients had other missense polymorphisms. CONCLUSIONS: Some individuals who have ABCR mutations may be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine. We urge further study of a larger cohort of patients with chloroquine/hydroxychloroquine retinopathy.

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60 ABCR Coding Alterations in Patients With Chloroquine and Hydroxychloroquine Retinopathy Exon Nucleotide* Amino Acid* Patient Number 1 2 3 4 5 6 7 8 6 635 Arg212His G/G G/G G/G G/G G/G G/G A/G G/G 10 1268 His423Arg A/A A/A A/A G/G A/A A/A A/A A/A 1269 His423His C/C C/C C/C C/C C/C C/T C/T C/C 20 2964 Leu988Leu C/C C/C C/C C/C C/C C/C C/T C/C 23 3385 Arg1129Cys† C/C C/C C/T† C/C C/C C/C C/C C/C 24 3602 Leu1201Arg† T/T T/T T/T T/T T/T T/T T/G† T/T 28 4203 Pro1401Pro C/C C/C C/C C/A C/A C/C C/C C/C 40 5603 Asn1868Ile A/A A/A A/A A/T A/T A/A A/A A/A 5682 Leu1894Leu G/G G/C G/C G/C G/C G/G C/C G/G 41 5814 Leu1938Leu A/A A/G A/G A/A A/A A/A G/G A/A 42 5844 Pro1948Pro A/A A/G A/G A/A A/A A/A G/G A/A 44 6069 Ile2023Ile C/C C/C C/C C/C C/C C/T C/C C/T 45 6249 Ile2083Ile C/C C/C C/C C/C C/C C/T C/C C/T 46 6285 Asp2095Asp T/T T/T T/T T/T T/T T/T C/C T/C 6320 Arg2107His† G/G G/G G/G G/G G/G G/G A/A† G/G 49 6764 Ser2255Ile G/G G/G G/G G/G G/G G/G G/T G/T *Standard amino acid and nucleotide abbreviations are used. Login to comment
62 mozygous for the transition 1268A3G, which encodes the missense substitution His423Arg. Login to comment

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

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

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102 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 2 106delT FS NS 0 0 1 Ͻ0.01 2 160 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 3 161G 3 A Cys54Tyr NS 0 0 6 Ͻ0.01 3 179C 3 T Ala60Val NS 0 0 2 Ͻ0.01 3 194G 3 A Gly65Glu NS 0 0 2 Ͻ0.01 3 223T 3 G Cys75Gly NS 0 0 2 Ͻ0.01 3 247delCAAA FS NS 0 0 2 Ͻ0.01 3 298C 3 T Ser100Pro NS 0 0 1 Ͻ0.01 5 454C 3 T Arg152Stop NS 0 0 2 Ͻ0.01 6 574G 3 A Ala192Thr NS 0 0 1 Ͻ0.01 6 618C 3 G Ser206Arg NS 0 0 3 Ͻ0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 Ͻ0.01 6 661delG FS NS 0 0 1 Ͻ0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 Ͻ0.01 6 746A 3 C Asp249Gly NS 0 0 1 Ͻ0.01 8 899C 3 A Thr300Asn NS 0 0 1 Ͻ0.01 8 997C 3 T Arg333Trp NS 0 0 1 Ͻ0.01 9 1140T 3 A Asn380Lys NS 0 0 1 Ͻ0.01 9 1222C 3 T Arg408Stop NS 0 0 1 Ͻ0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 Ͻ0.01 10 1344delG FS NS 0 0 1 Ͻ0.01 11 1411G 3 A Glu471Lys NS 0 0 3 Ͻ0.01 11 1513delATCAC FS NS 0 0 1 Ͻ0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 Ͻ0.01 13 1805G 3 A Arg602Gln NS 0 0 1 Ͻ0.01 13 1819G 3 T Gly607Trp NS 0 0 1 Ͻ0.01 13 1823T 3 A Phe608Ile NS 0 0 1 Ͻ0.01 13 1927G 3 A Val643Met NS 0 0 1 Ͻ0.01 14 1989G 3 T Trp663Stop NS 0 0 1 Ͻ0.01 14 2005delAT FS NS 0 0 3 Ͻ0.01 14 2041C 3 T Arg681Stop NS 0 0 2 Ͻ0.01 14 2147C 3 T Thr716Met NS 0 0 1 Ͻ0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 Ͻ0.01 15 2294G 3 A Ser765Asn NS 0 0 1 Ͻ0.01 15 2300T 3 A Val767Asp NS 0 0 2 Ͻ0.01 16 2385del16bp FS NS 0 0 1 Ͻ0.01 16 2453G 3 A Gly818Glu NS 0 0 1 Ͻ0.01 16 2461T 3 A Trp821Arg NS 0 0 1 Ͻ0.01 16 2546T 3 C Val849Ala NS 0 0 4 Ͻ0.01 16 2552G 3 A Gly851Asp NS 0 0 1 Ͻ0.01 16 2560G 3 A Ala854Thr NS 0 0 1 Ͻ0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 Ͻ0.01 18 2690C 3 T Thr897Ile NS 0 0 1 Ͻ0.01 18 2701A 3 G Thr901Ala NS 0 1 0 Ͻ0.01 18 2703A 3 G Thr901Arg NS 0 0 2 Ͻ0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 Ͻ0.01 20 2894A 3 G Asn965Ser NS 0 0 3 Ͻ0.01 19 2912C 3 A Thr971Asn NS 0 0 1 Ͻ0.01 19 2915C 3 A Thr972Asn NS 0 0 1 Ͻ0.01 20 2920T 3 C Ser974Pro NS 0 0 1 Ͻ0.01 20 2966T 3 C Val989Ala NS 0 0 2 Ͻ0.01 20 2977del8bp FS NS 0 0 1 Ͻ0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 Ͻ0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 Ͻ0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 Ͻ0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 Ͻ0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 Ͻ0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 Ͻ0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 Ͻ0.01 22 3323G 3 A Arg1108His NS 0 0 1 Ͻ0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 Ͻ0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 Ͻ0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 Ͻ0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 Ͻ0.01 26 3835delGATTCT FS NS 0 0 1 Ͻ0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 Ͻ0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 Ͻ0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 Ͻ0.01 28 4234C 3 T Gln1412stop NS 0 0 1 Ͻ0.01 29 4297G 3 A Val1433Ile NS 1 0 0 Ͻ0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 Ͻ0.01 30 4353 - 1g 3 t Splice site NS 0 0 1 Ͻ0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 Ͻ0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 Ͻ0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 Ͻ0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 Ͻ0.01 30 4531insC FS NS 0 0 2 Ͻ0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 Ͻ0.01 30 4539 ϩ 1g 3 t Splice site NS 0 0 1 Ͻ0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 Ͻ0.01 33 4733delGTTT FS NS 0 0 1 Ͻ0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 Ͻ0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 Ͻ0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 Ͻ0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 Ͻ0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 Ͻ0.01 36 5077G 3 A Val1693Ile NS 0 0 1 Ͻ0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 Ͻ0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 Ͻ0.01 36 5212del11bp FS NS 0 0 1 Ͻ0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 Ͻ0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 Ͻ0.01 37 5288delG FS NS 0 0 1 Ͻ0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 Ͻ0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 Ͻ0.01 39 5584 ϩ 5g 3 a Splice site 0.02 Yes 0 0 6 Ͻ0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 Ͻ0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 Ͻ0.01 40 5687T 3 A Val1896Asp NS 0 0 1 Ͻ0.01 40 5693G 3 A Arg1898His NS 0 0 1 Ͻ0.01 40 5714 ϩ 5g 3 a Splice site NS 0 0 1 Ͻ0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu Ͻ0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 Ͻ0.01 43 5917delG FS NS 0 0 1 Ͻ0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 Ͻ0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 Ͻ0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 Ͻ0.01 45 6148A 3 C Val2050Leu NS 1 0 0 Ͻ0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 Ͻ0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 Ͻ0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 Ͻ0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 Ͻ0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 Ͻ0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 Ͻ0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 Ͻ0.01 48 6707delTCACACAG FS NS 0 0 1 Ͻ0.01 48 6729 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 Ͻ0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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103 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 2 106delT FS NS 0 0 1 b0d;0.01 2 160 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 3 161G 3 A Cys54Tyr NS 0 0 6 b0d;0.01 3 179C 3 T Ala60Val NS 0 0 2 b0d;0.01 3 194G 3 A Gly65Glu NS 0 0 2 b0d;0.01 3 223T 3 G Cys75Gly NS 0 0 2 b0d;0.01 3 247delCAAA FS NS 0 0 2 b0d;0.01 3 298C 3 T Ser100Pro NS 0 0 1 b0d;0.01 5 454C 3 T Arg152Stop NS 0 0 2 b0d;0.01 6 574G 3 A Ala192Thr NS 0 0 1 b0d;0.01 6 618C 3 G Ser206Arg NS 0 0 3 b0d;0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 b0d;0.01 6 661delG FS NS 0 0 1 b0d;0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 b0d;0.01 6 746A 3 C Asp249Gly NS 0 0 1 b0d;0.01 8 899C 3 A Thr300Asn NS 0 0 1 b0d;0.01 8 997C 3 T Arg333Trp NS 0 0 1 b0d;0.01 9 1140T 3 A Asn380Lys NS 0 0 1 b0d;0.01 9 1222C 3 T Arg408Stop NS 0 0 1 b0d;0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 b0d;0.01 10 1344delG FS NS 0 0 1 b0d;0.01 11 1411G 3 A Glu471Lys NS 0 0 3 b0d;0.01 11 1513delATCAC FS NS 0 0 1 b0d;0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 b0d;0.01 13 1805G 3 A Arg602Gln NS 0 0 1 b0d;0.01 13 1819G 3 T Gly607Trp NS 0 0 1 b0d;0.01 13 1823T 3 A Phe608Ile NS 0 0 1 b0d;0.01 13 1927G 3 A Val643Met NS 0 0 1 b0d;0.01 14 1989G 3 T Trp663Stop NS 0 0 1 b0d;0.01 14 2005delAT FS NS 0 0 3 b0d;0.01 14 2041C 3 T Arg681Stop NS 0 0 2 b0d;0.01 14 2147C 3 T Thr716Met NS 0 0 1 b0d;0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 b0d;0.01 15 2294G 3 A Ser765Asn NS 0 0 1 b0d;0.01 15 2300T 3 A Val767Asp NS 0 0 2 b0d;0.01 16 2385del16bp FS NS 0 0 1 b0d;0.01 16 2453G 3 A Gly818Glu NS 0 0 1 b0d;0.01 16 2461T 3 A Trp821Arg NS 0 0 1 b0d;0.01 16 2546T 3 C Val849Ala NS 0 0 4 b0d;0.01 16 2552G 3 A Gly851Asp NS 0 0 1 b0d;0.01 16 2560G 3 A Ala854Thr NS 0 0 1 b0d;0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 b0d;0.01 18 2690C 3 T Thr897Ile NS 0 0 1 b0d;0.01 18 2701A 3 G Thr901Ala NS 0 1 0 b0d;0.01 18 2703A 3 G Thr901Arg NS 0 0 2 b0d;0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 b0d;0.01 20 2894A 3 G Asn965Ser NS 0 0 3 b0d;0.01 19 2912C 3 A Thr971Asn NS 0 0 1 b0d;0.01 19 2915C 3 A Thr972Asn NS 0 0 1 b0d;0.01 20 2920T 3 C Ser974Pro NS 0 0 1 b0d;0.01 20 2966T 3 C Val989Ala NS 0 0 2 b0d;0.01 20 2977del8bp FS NS 0 0 1 b0d;0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 b0d;0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 b0d;0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 b0d;0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 b0d;0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 b0d;0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 b0d;0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 b0d;0.01 22 3323G 3 A Arg1108His NS 0 0 1 b0d;0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 b0d;0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 b0d;0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 b0d;0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 b0d;0.01 26 3835delGATTCT FS NS 0 0 1 b0d;0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 b0d;0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 b0d;0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 b0d;0.01 28 4234C 3 T Gln1412stop NS 0 0 1 b0d;0.01 29 4297G 3 A Val1433Ile NS 1 0 0 b0d;0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 b0d;0.01 30 4353 afa; 1g 3 t Splice site NS 0 0 1 b0d;0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 b0d;0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 b0d;0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 b0d;0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 b0d;0.01 30 4531insC FS NS 0 0 2 b0d;0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 b0d;0.01 30 4539 af9; 1g 3 t Splice site NS 0 0 1 b0d;0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 b0d;0.01 33 4733delGTTT FS NS 0 0 1 b0d;0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 b0d;0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 b0d;0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 b0d;0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 b0d;0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 b0d;0.01 36 5077G 3 A Val1693Ile NS 0 0 1 b0d;0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 b0d;0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 b0d;0.01 36 5212del11bp FS NS 0 0 1 b0d;0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 b0d;0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 b0d;0.01 37 5288delG FS NS 0 0 1 b0d;0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 b0d;0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 b0d;0.01 39 5584 af9; 5g 3 a Splice site 0.02 Yes 0 0 6 b0d;0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 b0d;0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 b0d;0.01 40 5687T 3 A Val1896Asp NS 0 0 1 b0d;0.01 40 5693G 3 A Arg1898His NS 0 0 1 b0d;0.01 40 5714 af9; 5g 3 a Splice site NS 0 0 1 b0d;0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu b0d;0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 b0d;0.01 43 5917delG FS NS 0 0 1 b0d;0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 b0d;0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 b0d;0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 b0d;0.01 45 6148A 3 C Val2050Leu NS 1 0 0 b0d;0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 b0d;0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 b0d;0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 b0d;0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 b0d;0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 b0d;0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 b0d;0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 b0d;0.01 48 6707delTCACACAG FS NS 0 0 1 b0d;0.01 48 6729 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 b0d;0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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[hide] 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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74 Exon 10 is highly polymorphic and contains at least four polymorphic alterations: IVS9-14C→T, H423R (1268C→T), H423H (1269C→T), and IVS10+11delG. Login to comment
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] Partial paternal uniparental disomy (UPD) of chrom... Mol Vis. 2007 Jan 26;13:96-101. Riveiro-Alvarez R, Valverde D, Lorda-Sanchez I, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, Aguirre-Lamban J, Ramos C, Ayuso C
Partial paternal uniparental disomy (UPD) of chromosome 1 in a patient with Stargardt disease.
Mol Vis. 2007 Jan 26;13:96-101., [PMID:17277736]

Abstract [show]
PURPOSE: Stargardt disease (STGD) is the most common juvenile macular dystrophy, characterized by central visual impairment. All recessively inherited cases are thought to be due to mutations in the ABCA4 gene, mapped to 1p21-p13. METHODS: To describe a form of non-mendelian inheritance in a patient with STGD identified through the course of a conventional mutational screening performed on 77 STGD families. DNA from the patient and relatives was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray; results were confirmed by direct sequencing. Haplotype analyses, standard and high-resolution (HR) karyotypes, and multiplex ligation-dependent probe amplification (MLPA) were also performed. RESULTS: A patient with STGD caused by the homozygous p.Arg1129Leu mutation in the ABCA4 gene was found to be the daughter of a noncarrier mother and a father who was heterozygous for this change. Haplotype analysis suggested that no maternal ABCA4 allele was transmitted to the patient. Microsatellite markers spanning the entire chromosome 1 identified a homozygous region of at least 4.4 Mb, involving the ABCA4 gene. The cytogenetic study revealed normal female karyotype. Further evaluation with MLPA showed the patient had a normal dosage for both copies of the ABCA4 gene, thus suggesting partial paternal isodisomy but not a maternal microdeletion. CONCLUSIONS: We report that recessive STGD can rarely be inherited from only one unaffected carrier parent in a non-mendelian manner. This study also demonstrates that genomic alterations contribute to only a small fraction of disease-associated alleles for ABCA4.

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55 No other pathogenic mutation aside from two homozygous polymorphisms (p.His423Arg (c.1268A>G), IVS33+48 C>T) [16,17], were found in the screening of the gene using the ABCR400 microarray. Login to comment

[hide] Novel mutations in CRB1 and ABCA4 genes cause Lebe... Eur J Hum Genet. 2013 Nov;21(11):1266-71. doi: 10.1038/ejhg.2013.23. Epub 2013 Feb 27. Jonsson F, Burstedt MS, Sandgren O, Norberg A, Golovleva I
Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family.
Eur J Hum Genet. 2013 Nov;21(11):1266-71. doi: 10.1038/ejhg.2013.23. Epub 2013 Feb 27., [PMID:23443024]

Abstract [show]
This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

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89 Of the exonic variants, only p.N1868I and p.H423R were non-synonymous. Login to comment
90 Bioinformatics analysis predicted p.N1868I to be possibly damaging for protein function, whereas p.H423R was predicted to be benign. Login to comment
124 This result was not unexpected, as ABCA4 mRNA is expressed exclusively in retina.38 Table 3 ABCA4 sequence variants in STGD1 patient Position Nucleotide change Amino-acid change RefSNP SIFT PolyPhen Splice site effect MAF (minor allele frequency) Exon 10 c.1268A4G p.H423R rs3112831 Tolerated Benign - C &#bc; 0.246/538b Exon 28 c.4203C4A p.P1401P rs1801666 -a - - A &#bc; 0.005/12b Exon 40 c.5603A4T p.N1868I rs1801466 Possibly damaging Possibly damaging - A &#bc; 0.029/63b A &#bc; 0.139/115c Exon 40 c.5682G4C p.L1894L rs1801574 - - - G &#bc; 0.219/478b - Intron 3 c.302 &#fe; 26A4G - rs2297634 - - None T &#bc; 0.470/1026b Intron 7 c.769-32T4C - rs526016 - - None G &#bc; 0.228/497b Intron 9 c.1240-14C4T - rs4147830 - - None G &#bc; 0.477/1041b Intron 13 c.1761-54G4A - rs4147833 - - Cryptic site T &#bc; 0.377/824b Intron 26 c.3863-73_3863-64delA - rs4147892 - - None NAb Intron 33 c.4773 &#fe; 3A4G New variant - - Weak NAb G &#bc; 0.009/113c Intron 38 c.5461-10T4C rs1800728 - - Weak NAb C &#bc; 0.000/116c Intron 38 c.5461-51delA rs4147899 - - none &#bc; 0.215/469b aNot predictable. 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

[hide] Next-generation sequencing of ABCA4: High frequenc... Exp Eye Res. 2015 Nov 22;145:93-99. doi: 10.1016/j.exer.2015.11.011. Sciezynska A, Ozieblo D, Ambroziak AM, Korwin M, Szulborski K, Krawczynski M, Stawinski P, Szaflik J, Szaflik JP, Ploski R, Oldak M
Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe.
Exp Eye Res. 2015 Nov 22;145:93-99. doi: 10.1016/j.exer.2015.11.011., [PMID:26593885]

Abstract [show]
Variation in the ABCA4 locus has emerged as the most prevalent cause of monogenic retinal diseases. The study aimed to discover causative ABCA4 mutations in a large but not previously investigated cohort with ABCA4-related diseases originating from Central Europe and to refine the genetic relevance of all identified variants based on population evidence. Comprehensive clinical studies were performed to identify patients with Stargardt disease (STGD, n = 76) and cone-rod dystrophy (CRD, n = 16). Next-generation sequencing targeting ABCA4 was applied for a widespread screening of the gene. The results were analyzed in the context of exome data from a corresponding population (n = 594) and other large genomic databases. Our data disprove the pathogenic status of p.V552I and provide more evidence against a causal role of four further ABCA4 variants as drivers of the phenotype under a recessive paradigm. The study identifies 12 novel potentially pathogenic mutations (four of them recurrent) and a novel complex allele p.[(R152*; V2050L)]. In one third (31/92) of our cohort we detected the p.[(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Causative ABCA4 mutations account for 79% of STGD and 31% of CRD cases. A combination of p.[(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression. The comprehensive, population-specific study expands our knowledge on the genetic landscape of retinal diseases.

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80 Thorough search of the literature and four distinct population-derived exome/genome variant databases, including a database of the Polish population showed that four of the ABCA4 variants, i.e. p.R212H, p.H423R, c.6282&#fe;7G>A and p.S2255I have a high frequency (at least 3%) in the general population (Allikmets et al., 1997; Maugeri et al., 1999; Rivera et al., 2000). Login to comment
81 Additionally, none of the ABCA4 variants occurred more often among patients than control subjects (p > 0.05) and p.H423R was found significantly less prevalent in patients than in control subjects. Login to comment
142 ABCA4 variant Patients Controls Present study ZGM 1000 Genomes ESP6500 ExAC c.635G>A 2.17% 3.82% 5.17% 3.41% 3.79% p.R212H (4/184) (45/1178) (52/1006) (293/8600) (2791/73,710) p &#bc; 0.39 p &#bc; 0.09 p &#bc; 0.48 p &#bc; 0.34 c.1268A>G 20.11% 29.90% 29.13% 30.94% 29.66% p.H423R (37/184) (354/1184) (293/1006) (2661/8600) (22,085/74,456) p < 0.01 p < 0.0001 p < 0.0001 p < 0.0001 c.6282&#fe;7G>A 4.89% 7.84% 5.86% 6.78% 5.92% splice site mutation (9/184) (93/1186) (59/1006) (583/8600) (4378/74,008) p &#bc; 0.18 p &#bc; 0.73 p &#bc; 0.39 p &#bc; 0.67 c.6764G>T 2.17% 4.41% 4.57% 4.65% 3.77% p.S2255I (4/184) (52/1178) (46/1006) (400/8600) (2802/74,338) p &#bc; 0.23 p &#bc; 0.16 p &#bc; 0.16 p &#bc; 0.35 c.1654G>A 1.09% 1.01% 0.10% 0.37% 0.37% p.V552I (2/184) (12/1188) (1/1006) (32/8600) (273/74,448) p &#bc; 1 p &#bc; 0.06 p &#bc; 0.34 p &#bc; 0.32 ZGM: exome data for the Polish population; 1000 Genomes: 1000 Genomes Project (http://www.1000genomes.org/); ESP6500: NHLBI GO Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/); ExAC: Exome Aggregation Consortium (http://exac.broadinstitute.org/); The number of variant and total alleles detected is given in brackets. Login to comment