ABCMdb

PMID: 24677105

Burke TR, Duncker T, Woods RL, Greenberg JP, Zernant J, Tsang SH, Smith RT, Allikmets R, Sparrow JR, Delori FC
Quantitative fundus autofluorescence in recessive Stargardt disease.
Invest Ophthalmol Vis Sci. 2014 May 1;55(5):2841-52. doi: 10.1167/iovs.13-13624., [PubMed]

Sentences

No. Mutations Sentence Comment

47 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu In some cases where no mutations were detected by the array, or in more recently recruited patients, the next generation sequencing of the entire ABCA4 open reading frame and adjacent intronic sequences was performed on the Roche 454 platform.30 The four most common mutations found in six or more patients were: G1961E (12 patients from 11 families); L541P/ A1038V (eight patients from five families); L2027F (six patients from five families); and P1380L (six patients from six families). Login to comment 48 ABCA4 p.Arg1640Trp ABCA4 p.Arg2030Gln ABCA4 p.Gly851Asp ABCA4 p.Tyr1557Cys Four other mutations were found in two to four patients: R1640W (four patients from three families); Y1557C (two patients from one family); G851D (two patients from one family); and R2030Q (two patients from two families). Login to comment 49 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro For the purposes of analyses reported below, we will refer to those eight mutations as the ''more common mutations.`` In two patients (two families), A1038V was present in a compound heterozygous state with other mutations while not as a complex allele with L541P (Table 1). Login to comment 77 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro [L541P; A1038V] 639 627 1.9 2.0 1.2 M 7 1 0.30 0.18 - I p. Login to comment 78 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Pro1380Leu [L541P; A1038V] 413 1.9 2 F 25 11 0.80 0.80 II II p.G863A; c.5898&#fe;1G > A 710 675 3.4 3.3 3 M 11 6 0.80 0.70 I - p.G1961E; p.P1380L 267 2.3 4.1 M 35 10 0.30 0.18 I - p.G1961E; p. Login to comment 79 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro [L541P; A1038V] 426 2.1 4.2 M 35 10 0.40 0.48 I I p.G1961E; p. Login to comment 80 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Gln636His ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu ABCA4 p.Thr972Asn ABCA4 p.Arg2077Trp ABCA4 p.Glu1252* ABCA4 p.Arg1161Ser [L541P; A1038V] 356 354 1.7 1.8 5 F 14 1 0.60 0.60 II II p.L2027F; p.T972N 737 718 2.3 2.6 6 M 45 31 1.00 0.88 I I p.G1961E; p.P1380L 623 543 4.2 4.0 7 F 42 5 0.30 CF - I p.E1252* 557 2.1 8 M 15 4 0.80 0.80 II II p.L2027F; p.R2077W 728 697 3.2 3.2 9 F 24 2 0.60 0.40 II II p.R1161S 571 647 3.8 3.5 10 M 46 15 1.30 1.30 I I p.G1961E; p.Q636H 394 351 2.3 2.4 11.1 M 12 2 1.00 1.00 II - p. Login to comment 81 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp [L541P; A1038V]; p.R1640W 911 3.3 11.2 F 10 4 1.00 1.00 II - p. Login to comment 82 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Cys54Tyr ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Gly851Asp ABCA4 p.Gly851Asp ABCA4 p.Tyr1557Cys ABCA4 p.Tyr1557Cys [L541P; A1038V]; p.R1640W 850 4.4 12 F 27 9 1.30 1.00 - III p.P1380L; p.P1380L 577 4.8 13 F 39 8 0.12 0.00 - I c.250_251insCAAA 616 2.3 14 M 23 4 0.88 0.60 - II p.C54Y 535 5.1 15.1 M 49 17 1.00 0.88 I I p.Y1557C 646 604 4.1 3.9 15.2 M 46 7 0.10 0.48 I I p.Y1557C 456 508 2.6 2.3 16.1 F 27 14 0.88 0.88 III III p.L2027F; p.G851D 448 459 6.0 6.3 16.2 F 29 19 1.30 1.18 III III p.L2027F; p.G851D 538 569 7.4 7.9 17 M 22 18 1.30 1.00 III III p.P1380L; p.R2030Q 434 411 5.7 6.0 18 M 37 16 0.70 0.70 I I p.G1961E; p.G1961E 281 279 2.6 2.2 19 F 33 5 0.88 0.70 I I p.G1961E; c.4540-2A > G 412 420 2.5 2.8 20 F 26 12 0.60 0.60 - I p.G1961E; p. Login to comment 83 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Ala1598Asp ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Ala1773Val [L541P; A1038V] 398 2.4 21 F 45 31 0.88 0.88 I I p.R1640W 647 613 2.6 2.8 22 M 43 7 1.00 0.00 - III p.A1773V; p.G1591G 640 6.9 23 F 41 1 0.10 CF II II p.P1486L; p.A1598D 613 572 6.0 6.5 24 F 19 4 0.60 0.70 I - p.G1961E; p.P1380L 368 2.4 25 F 23 4 0.88 0.80 - I p. Login to comment 84 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Cys2150Tyr ABCA4 p.Cys2150Tyr ABCA4 p.Arg1108His ABCA4 p.Arg1108His ABCA4 p.Arg1129Cys ABCA4 p.Ala854Thr ABCA4 p.Met1882Ile ABCA4 p.Ala848Asp [A854T; A1038V]; p.C2150Y 512 2.3 26 F 52 1 0.70 0.48 I - p.R212C 722 2.0 27 F 52 13 1.00 1.00 - I p.A1038V; p.A848D 459 4.1 28 M 20 5 0.30 0.40 I - p.L2027F; p.R1108H 507 2.3 29 M 23 7 1.00 1.00 I I p.G1961E; p.R2030Q 334 347 2.4 2.0 30 M 44 26 0.70 0.70 - II p.P1380L; p.R1108H 453 4.7 31 F 30 22 1.00 1.30 - I p.G1961E; c.6005&#fe;1G > T 428 2.3 32 M 12 8 0.40 0.40 I - p.W821R; p.C2150Y 306 2.0 33 F 20 9 0.88 0.88 III III p.R602W; p.M1882I 650 655 2.6 2.5 34 F 47 4 0.40 0.40 I - p.G1961E; p.R1129C 400 2.5 35 F 19 3 0.70 0.48 II II p. Login to comment 85 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg1108Cys ABCA4 p.Gln1412* [L541P; A1038V]; p.L2027F 733 749 3.9 4.0 36 F 20 7 0.88 1.00 II II p.R1640W 571 552 3.4 3.8 37 F 12 3 0.80 0.80 I I p.R1108C; p.Q1412* 536 501 1.7 1.7 * All subjects were white, except for patients 10, 22, and 36 who were Indian, Hispanic, and black, respectively. Login to comment 135 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Comparing each of the four most common mutations separately with healthy eyes, G1961E (P &#bc; 0.001); L541P/ A1038V (P < 0.001); L2027F (P < 0.001); and P1380L (P &#bc; 0.024) eyes had qAF8 that was significantly higher than in FIGURE 2. Login to comment 146 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Gly851Asp When corrected for age (P &#bc; 0.04) and sex (P &#bc; 0.004), compared with all other patients who did not have that particular mutation, the mutations L2027F (P &#bc; 0.009) and L541P/A1038V (P &#bc; 0.015) were associated with higher qAF8, while A1038V (when not in conjunction with L541P, P &#bc; 0.06); G851D (P &#bc; 0.006); and G1961E (P < 0.001) were associated with lower qAF8 in this sample. Login to comment 152 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Genotype-Phenotype Relations (TF) When compared separately with healthy eyes, three of the four most common mutations, L541P/A1038V (P < 0.001); L2027F (P < 0.001); and P1380L (P &#bc; 0.001), had TF that was significantly higher than in healthy eyes, when corrected for age. Login to comment 153 ABCA4 p.Gly1961Glu Conversely, G1961E did not have higher TF than healthy eyes (P &#bc; 0.61). Login to comment 155 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu ABCA4 p.Gly851Asp When compared with all other patients who did not have that particular mutation, G851D (P < 0.001) and P1380L (P &#bc; 0.008) were associated with higher TF, while G1961E (P &#bc; 0.01) was associated with lower TF in this sample. Login to comment 180 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Gly851Asp ABCA4 p.Tyr1557Cys The mutations were confirmed in six or more patients (G1961E, L541P/A1038V, L2027F, and P1380L) or in two to four patients (R1640W, Y1557C, G851D, and R2030Q). Login to comment 181 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Also shown is mutation A1038V in a compound heterozygous state with other mutations while not as a complex allele with L541P. Login to comment 221 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu ABCA4 p.Gly851Asp In our cohort, the mutations G851D and P1380L had high AF texture while G1961E was associated with lower AF texture. Login to comment 226 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Gly851Asp For example, based on our cross-sectional data, the mutations L2027F and L541P/A1038V seem to confer a faster rate of accumulation, whereas G1961E and G851D seems to confer a slower increase (Fig. 5). Login to comment 227 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro The complex allele L541P/A1038V involves missense mutations in both the exocytoplasmic domain-1 and nucleotide FIGURE 7. Login to comment 230 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro binding domain (NBD)-1 and confers severe STGD1 with relatively early onset of retina-wide disease.44-47 In our study, the L541P/A1038V complex allele was in some patients associated with high qAF8 even at young ages, while in other patients, particularly in those compound heterozygous for L541P/A1038V and G1961E, qAF8 values were relatively lower (Fig. 5). Login to comment 232 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Thus it is likely that in these cases, the lower qAF values do not reflect a decrease in qAF after an earlier rapid elevation, but rather a slower increase in qAF8 due to the presence of the G1961E allele (L541P/A1038V &#fe; G1961E). Login to comment 233 ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Additional missense mutations found to associate with elevated qAF8 compared with other mutations in our sample were L2027F and P1380L. Login to comment 234 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Arg2077Trp The L2027F mutation causes an amino acid change in NBD-2 and confers reduced ATP binding.11,48 P1380L is also a severe mutation and is suggested to cause either impaired ATP binding11 or altered transport of ABCA4 protein across the outer segment membrane.46 When P1380L is carried in compound heterozygosity with R2077W, autosomal recessive cone-rod dystrophy results.49 When harbored as a homozygous mutation or as a compound heterozygous mutation with R2030Q or IVS40 &#fe; 5G>A, the mutation is associated with central atrophy and peripapillary disease, the latter being an uncommon phenotype.50 The missense mutation G1961E in exon 42 of the ABCA4 gene is the most common ABCA4 mutation.51 This sequence change results in a glycine to glutamate substitution within the NBD-2 of the protein.11,45 The G1961E allele always cosegregates with the disease in families.45,52 Nevertheless, the G1961E mutation in ABCA4 is perplexing since in an in vitro assay this mutation conferred a markedly aberrant decrease in all-trans-retinal stimulated ABCA4 ATPase activity,11 yet it is considered to be associated with mild disease. Login to comment 235 ABCA4 p.Gly1961Glu For instance, in Fishman`s28 original classification of 29 STGD1 patients into three clinical phenotypes, patients with the G1961E variation on one ABCA4 allele were assigned to the mildest (Fishman I) of the three. Login to comment 237 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu The G1961E variant was reported to confer a tendency toward later disease onset51 (though not in our sample), and relatively long delay before retina-wide changes.46 Also characteristic of this mutation is an absence of a dark choroid.28 A dark choroid in fluorescein angiography is generally attributed to high content and absorption by lipofuscin in the RPE, a feature that also confers a vermillion fundus appearance.19 Thus, absence of dark choroid is considered to reflect less pronounced lipofuscin accumulation; this interpretation is consistent with our finding that in the presence of the G1961E mutation, qAF levels outside the parafovea are lower when compared with other ABCA4 mutations. Login to comment 238 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In fundus AF images, the G1961E allele in both the homozygous and compound heterozygous state is commonly associated with bull`s eye maculopathy.53 Taken together, the clinical features of the disease associated with G1961E indicate a phenotype chiefly confined to cone-rich fovea and parafovea (central macula). Login to comment 243 ABCA4 p.Gly1961Glu Perhaps abnormal accretion of bisretinoid lipofuscin in photoreceptor inner and outer segments in the presence of the G1961E mutation is a feature deserving future investigation. Login to comment 429 ABCA4 p.Gly1961Glu Burke TR, Fishman GA, Zernant J, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Login to comment 435 ABCA4 p.Gly1961Glu Cella W, Greenstein VC, Zernant-Rajang J, et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull`s eye maculopathy. Login to comment