ABCMdb

PMID: 26551331

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

Sentences

No. Mutations Sentence Comment

26 ABCA4 p.Leu541Pro [L541P;A1038V] 0.18 0.00 OD 357 339 S1.4 M 49.2 White Father c.768&#fe;358C>T 0.00 0.00 OS 322 339 S1.5 M 24.7 White Half-brother p. Login to comment 27 ABCA4 p.Leu541Pro [L541P;A1038V] 0.00 0.00 n/a 264 n/a S1.6 M 9.7 White Brother p. Login to comment 28 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Cys54Tyr ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Thr1526Met ABCA4 p.Thr1526Met ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Lys346Thr ABCA4 p.Arg408* ABCA4 p.Gly851Asp ABCA4 p.Thr1117Ile ABCA4 p.Arg1161Ser ABCA4 p.Arg1161Ser ABCA4 p.Arg2030* ABCA4 p.Gln2220* ABCA4 p.Trp855* ABCA4 p.Cys698Tyr ABCA4 p.Cys698Tyr [L541P;A1038V] 0.10 0.10 OS n/a 141 S2.2 F 44.4 Indian Mother c.6729&#fe;5_&#fe;19del 0.10 0.00 OS 257 291 S2.3 M 56.2 Indian Father p.G1961E 0.00 0.00 OD 475 431 S3.4 F 54.1 White Mother p.G863A 0.00 0.00 OS 459 451 S3.5 F 82.0 White Grandmother p.G863A 0.00 0.00 OD n/a n/a S4.2 F 44.6 White Mother p.W855* 0.00 0.00 OD 330 n/a S4.3 M 40.9 White Father p.T1526M 0.00 0.00 OS 283 271 S5.2 F 71.5 White Sister p.C698Y 0.00 0.10 OD n/a n/a S5.3 F 67.5 White Sister c.2160&#fe;1G>C 0.00 0.00 OS n/a n/a S5.4 F 62.9 White Sister p.C698Y 0.00 0.00 OD n/a n/a S6.2 M 54.9 Black Brother p.T1526M 0.10 0.00 OS 477 423 S7.2 F 48.9 White Mother c.5196&#fe;1G>A 0.00 0.00 OS 443 415 S8.2 F 59.6 White Mother p.K346T 0.00 0.00 OD 546 483 S8.3 M 54.6 White Father p.T1117I 0.10 0.10 OD 289 n/a S9.2 F 51.5 White Mother c.5196&#fe;1137G>A 0.00 0.00 n/a 302 n/a S9.3 M 57.8 White Father p.C54Y 0.00 0.00 OS 419 375 S10.2 M 24.1 Indian Brother p.Q2220* 0.00 0.00 OD 227 227 S11.2 F 40.0 Asian Mother c.5923del 0.00 0.18 OD 229 191 S11.3 M 40.1 Asian Father p.R408* 0.00 0.00 OD 195 178 S12.2 F 53.2 White Mother p.L2027F 0.00 0.00 n/a 355 309 S13.2 F 49.8 White Mother p.R1161S 0.00 0.00 OS 367 372 S13.3 M 22.3 White Brother p.R1161S 0.00 0.00 OD 202 206 S14.2 F 67.0 White Mother p.P1380L 0.00 0.00 OD n/a n/a S14.3 F 24.4 White Sister p.P1380L 0.00 0.00 OS n/a 163 S15.3 F 26.8 White Sister c.3050&#fe;5G>A 0.00 0.00 n/a 293 281 S16.2 M 53.7 Black Father c.4253&#fe;5G>T 0.00 0.00 n/a n/a 204 S17.2 F 60.0 Hispanic Mother p.A1038V 0.00 0.00 n/a 247 n/a S18.2 F 41.8 Indian Father c.5917del 0.00 0.00 OD n/a 194 S18.3 M 48.6 Indian Mother c.859-9T>C 0.00 0.00 OD 253 215 S18.4 F 12.9 Indian Sister c.5917del 0.00 0.00 OD 84 93 S19.4 F 58.5 White Mother p.L2027F 0.00 0.00 OD 205 n/a S19.5 M 61.6 White Father p.G851D 0.10 0.10 OD n/a n/a S20.2 F 41.5 White Mother c.5312&#fe;1G>A 0.00 0.00 n/a 335 351 S20.3 M 39.0 White Father p.R2030* 0.00 0.10 n/a 442 n/a S21.3 F 53.1 White Mother p.G1961E 0.00 0.00 OD 490 488 S22.3 M 46.3 White Father p.L2027F 0.00 0.00 OS 386 376 S22.4 F 47.1 White Mother p. Login to comment 29 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Arg2107His [L541P;A1038V] 0.00 0.00 OS 342 326 S23.2 F 37.4 White Sister p.G1961E 0.00 0.00 OS 220 n/a S24.2 F 37.5 White Daughter c.247_250dup 0.00 0.00 OD 298 288 S25.3 F 49.9 Black Mother p.R2107H 0.88 0.10 n/a n/a 385 S26.3 F 58.2 White Mother p.G1961E 0.00 0.00 OD 238 297 S26.4 M 57.2 White Father p. Login to comment 30 ABCA4 p.Leu541Pro [L541P;A1038V] 0.18 1.30 OS 312 279 S26.3 M 17.4 White Brother p. Login to comment 31 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu [L541P;A1038V] 0.10 0.00 OS 174 143 S27.2 F 46.2 White Mother p.P1380L 0.00 0.10 OD 379 320 S27.3 M 47.3 White Father p.G1961E 0.00 0.00 OD 413 384 S27.4 F 17.4 White Sister p.P1380L 0.00 0.00 OS 184 189 S28.2 F 58.9 White Mother p. Login to comment 32 ABCA4 p.Ala854Thr ABCA4 p.Ala848Asp ABCA4 p.Arg1300* [A854T;A1038V] 0.00 0.00 OS n/a 449 S29.2 F 26.8 White Daughter p.A848D 0.00 0.00 OD n/a 246 S30.2 F 63.5 Hispanic Sister p.R1300* 0.00 0.00 n/a n/a n/a S31.2 M 49.7 White Father p. Login to comment 34 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Arg2030Gln ABCA4 p.Trp821Arg ABCA4 p.Trp1408Arg [W1408R;R1640W] 0.00 0.00 n/a n/a 336 S33.2 F 46.5 White Mother p.G1961E 0.00 0.00 OD 422 n/a S33.3 M 48.0 White Father p.R2030Q 0.00 0.00 OD 298 n/a S34.2 M 50.3 White Brother p.G1961E 0.00 0.48 n/a 394 368 S35.2 F 55.7 White Mother p.G1961E 0.00 0.00 OS 328 362 S35.3 M 57.4 White Father c.3050&#fe;5G>A 0.00 0.00 OD n/a 265 S36.2 F 59.4 Hispanic Mother p.G1961E 0.00 0.00 OS 380 374 S37.2 F 55.1 White Mother p.G1961E 0.00 0.00 n/a n/a 352 S38.2 F 48.9 White Mother p.W821R 0.00 0.00 OD 252 279 tion in psychophysical and electrophysiological tests,21 and may demonstrate moderate to severe fundus changes.17,22 The increased accumulation of lipofuscin in the RPE of patients with biallelic mutations in ABCA4 has been documented by histology,9 by spectrofluorometry,23 and more recently by quantitative autofluorescence (qAF).24 It is still unknown, however, whether individuals heterozygous for ABCA4 mutations also have elevated lipofuscin levels due to reduced ABCA4 activity. Login to comment 62 ABCA4 p.Gly1961Glu ABCA4 p.Cys54Tyr ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Pro1486Leu ABCA4 p.Cys2150Tyr ABCA4 p.Thr897Ile ABCA4 p.Lys1547* ABCA4 p.Asn965Tyr ABCA4 p.Gln1412* Continued Subject Sex Age Race/ Ethnicity Relationship to Proband ABCA4 Mutation BCVA, logMAR Eye Segmented qAF8 OD OS OD OS S38.3 M 50.9 White Father p.C2150Y 0.00 0.00 OS 336 380 S39.3 F 42.5 White Mother c.5714&#fe;5G>A 0.00 0.00 n/a 462 393 S39.4 F 18.4 White Sister c.5714&#fe;5G>A 0.00 0.00 n/a 222 212 S40.2 F 50.1 White Mother p.R2030Q 0.00 0.00 OD 433 n/a S40.3 M 48.8 White Father p.K1547* 0.00 0.00 OS n/a 477 S41.2 F 60.3 White Mother p.C54Y 0.00 0.00 OS n/a n/a S42.2 F 44.5 White Mother p.Q1412* 0.10 0.00 OS 264 291 S42.3 M 44.2 White Father p.R1108C 0.30 0.18 OD 264 232 S43.2 F 44.9 White Mother p.G1961E 0.00 0.00 OS 404 n/a S44.3 M 37.1 Asian Father c.4248_4250del 0.00 0.00 OD 307 317 S45.2 F 66.3 White Mother p.N965Y 0.18 0.40 n/a n/a n/a S45.3 M 68.0 White Father p.P1486L 0.00 0.00 n/a n/a n/a S46 M 32.3 White Spouseߤ p.T897I 0.12 0.12 OD 194 200 BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye; qAF8, average quantitative autofluorescence of the 8 measurement sites from all available images per eye; n/a, not available. Login to comment 66 ABCA4 p.Leu541Pro [L541P;A1038V] c.768&#fe;358C>T 0.54 0.60 639 627 P 1.2&#a7; M 7.0 White p. Login to comment 67 ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Thr1526Met ABCA4 p.Thr1526Met ABCA4 p.Lys346Thr ABCA4 p.Thr1117Ile ABCA4 p.Trp855* ABCA4 p.Ser2235Pro [L541P;A1038V] c.768&#fe;358C>T 0.30 0.18 n/a 413 P 2.1ߤ M 17.9 Indian p.G1961E c.6729&#fe;5_&#fe;19del 0.70 0.88 340 363 P 3.1&#a7; F 25.1 White p.G863A c.5898&#fe;1G>A 0.80 0.80 710 675 P 3.2ߤ F 18.9 White p.G863A c.5898&#fe;1G>A 0.00 0.00 465 431 P 3.3 F 24.4 White p.G863A c.5898&#fe;1G>A 0.18 0.00 507 467 P 4.1 M 9.0 White p.W855* p.T1526M 1.00 1.00 538 n/a P 5.1 F 67.0 White p.C54Y c.2160&#fe;1G>C CF HM n/a n/a P 6.1 M 46.0 Black p.T1526M 0.30 0.80 n/a n/a P 7.1 F 25.3 White c.5196&#fe;1G>A p.S2235P 1.00 1.30 420 317 P 8.1 M 17.0 White p.K346T p.T1117I 1.30 0.70 871 828 P 9.1 M 21.5 White p.C54Y c.5196&#fe;1137G>A 0.18 0.18 609 608 P 10.1 M 31.0 Indian c. Login to comment 68 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Val989Ala ABCA4 p.Asn96Asp ABCA4 p.Asn96Asp ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Arg2077Trp ABCA4 p.Arg408* ABCA4 p.Gly851Asp ABCA4 p.Gly851Asp ABCA4 p.Gly851Asp ABCA4 p.Gly1441Asp ABCA4 p.Arg1161Ser ABCA4 p.Arg2030* ABCA4 p.Gln2220* [66G>A;859-9T>C] p.Q2220* CF 1.30 n/a n/a P 11.1 M 15.0 Asian p.R408* c.5935del 1.10 1.30 n/a n/a P 12.1&#a7; M 15.1 White p.L2027F p.R2077W 0.80 0.80 728 697 P 13.1&#a7; F 23.8 White p.R1161S 0.60 0.40 571 647 P 14.1&#a7; F 27.3 White p.P1380L p.P1380L 1.30 1.00 n/a 577 P 15.1 M 17.0 White p.G1961E c.3050&#fe;5G>A 0.88 0.88 n/a n/a P 15.2 F 22.0 White p.G1961E c.3050&#fe;5G>A 0.88 0.88 n/a n/a P 16.1 F 19.1 Black p.V989A c.4253&#fe;5G>T 0.30 0.40 97 n/a P 17.1 F 21.8 Hispanic p.A1038V p.G1441D 0.70 0.88 551 528 P 18.1 M 22.0 Indian c.859-9T>C c.5917del 0.88 0.88 527 n/a P 19.1&#a7; F 27.2 White p.G851D p.L2027F 0.88 0.88 448 459 P 19.2&#a7; F 29.2 White p.G851D p.L2027F 1.30 1.18 538 569 P 19.3 F 34.2 White p.G851D p.L2027F 1.00 1.30 442 n/a P 20.1 F 9.5 White c.5312&#fe;1G>A p.R2030* 0.88 0.70 998 929 P 21.1ߤ F 24.6 White p.N96D p.G1961E 0.30 0.18 513 549 P 21.2ߤ F 20.9 White p.N96D p.G1961E 0.30 0.40 397 355 P 22.1 M 8.0 White p. Login to comment 69 ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe [L541P;A1038V] p.L2027F n/a n/a P 22.2 M 13.9 White p. Login to comment 70 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Leu2027Phe ABCA4 p.Glu526Ala ABCA4 p.Glu526Ala [L541P;A1038V] p.L2027F 0.30 0.40 591 608 P 23.1ߤ F 26.0 White p.G1961E c.5196&#fe;1056A>G 0.40 0.70 379 344 P 24.1 F 52.0 White c.247_250dup 0.80 0.00 n/a n/a P 25.1 F 26.0 Black p.E526A p.R2107H 0.48 0.00 507 536 P 25.2 F 25.9 Black p.E526A p.R2107H 0.18 0.00 461 468 P 26.1&#a7; F 25.6 White p. Login to comment 71 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [L541P;A1038V] p.G1961E 0.60 0.60 n/a 398 P 26.2 F 19.7 White p. Login to comment 72 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Pro1380Leu [L541P;A1038V] p.G1961E 0.60 0.54 320 307 P 27.1&#a7; F 18.8 White p.P1380L p.G1961E 0.60 0.70 368 n/a P 28.1&#a7; F 22.9 White p. Login to comment 73 ABCA4 p.Ala1038Val ABCA4 p.Cys2150Tyr ABCA4 p.Ala854Thr ABCA4 p.Ala848Asp ABCA4 p.Arg1300* ABCA4 p.Phe938Ser [A854T;A1038V] p.C2150Y 0.88 0.80 n/a 512 P 29.1&#a7; F 52.2 White p.A848D p.A1038V 1.00 1.00 n/a 459 P 30.1 F 40.3 Hispanic p.F938S p.R1300* 0.40 1.18 524 451 P 31.1 M 6.0 White p. Login to comment 74 ABCA4 p.His1118Tyr [Y245*;V767D] 1.30 1.30 n/a n/a P 32.1 F 32.0 Hispanic p.H1118Y p. Login to comment 75 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys2150Arg ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Arg2030Gln ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Cys2150Tyr ABCA4 p.Trp1408Arg ABCA4 p.Arg408* ABCA4 p.Arg408* ABCA4 p.Lys1547* ABCA4 p.Asn965Tyr ABCA4 p.Ala1773Val ABCA4 p.Gln1412* [W1408R;R1640W] 1.00 1.00 n/a n/a P 33.1&#a7; M 23.0 White p.R2030Q p.G1961E 1.00 1.00 334 347 P 34.1 M 46.9 White p.C1490Y p.G1961E 0.40 0.30 376 384 P 35.1ߥ M 24.8 White c.3050&#fe;5G>A p.G1961E 0.00 0.00 381 451 P 36.1ߥ F 29.3 Hispanic p.L541P p.G1961E 0.40 0.40 479 487 P 37.1ߤ F 24.7 White p.G1961E p.C2150R 0.88 0.88 405 396 P 38.1&#a7; M 11.7 White p.W821R p.C2150Y 0.40 0.40 306 n/a P 39.1 F 12.8 White p.P1380L c.5714&#fe;5G>A 0.60 0.40 558 573 P 39.2 M 14.1 White p.P1380L c.5714&#fe;5G>A 0.88 0.88 395 462 P 40.1ߤ F 16.2 White p.K1547* p.R2030Q 0.70 0.40 481 513 P 41.1 F 19.0 White p.C54Y 0.88 0.88 n/a n/a P 42.1ߤ F 13.0 White p.R1108C p.Q1412* 1.30 1.00 511 528 P 43.1ߤ M 17.4 White p.A1773V p.G1961E 0.88 0.88 340 366 P 44.1 M 14.0 Asian p.R408* c.4248_4250del 1.30 1.30 n/a n/a P 44.2 F 7.0 Asian p.R408* c.4248_4250del 1.30 1.30 n/a n/a P 45.1 F 42.4 White p.N965Y p.P1486L 0.10 0.40 n/a n/a BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye; qAF8, average quantitative autofluorescence of the 8 measurement sites from all available images per eye; n/a, not available. Login to comment 110 ABCA4 p.Gly1961Glu The following ABCA4 mutations were frequently present in our cohort: p.G1961E in 11 carriers, p. Login to comment 111 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu [L541P; A1038V] in six carriers, p.P1380L in four carriers, and p.L2027F in three carriers. Login to comment 123 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu Quantitative autofluorescence intensities associated with 4 common ABCA4 mutations: p.G1961E, p.P1380L, p. Login to comment 124 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe [L541P; A1038V], p.L2027F. Login to comment 136 ABCA4 p.Gly1961Glu We previously demonstrated that STGD1 patients carrying the p.G1961E mutation on one allele have relatively lower qAF8 levels compared to patients with p. Login to comment 137 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu [L541P; A1038V], p.P1380L, and p.L2027F mutations (and no p.G1961E mutation on the other allele).24 To determine whether similar differences in the segregation of qAF8 levels could also be observed for ABCA4 mutations in carriers and whether specific ABCA4 mutations may be associated with higher qAF8 levels, we plotted qAF values for carriers and affected patients who carried one of the four most common mutations (p.G1961E, p. Login to comment 138 ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu [L541P;A1038V], p.P1380L, and p.L2027F) (Fig. 4). Login to comment 145 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu Color-coded maps of quantitative fundus autofluorescence and inheritance patterns of families carrying ABCA4 mutations p.P1380L (family 39) p.G1961E; p. Login to comment 146 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro [L541P, A1038V] (family 26), p. Login to comment 147 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Pro1380Leu [L541P; A1038V] (family 1), and p.G1961E; p.P1380L (family 27). Login to comment 162 ABCA4 p.Gly1961Glu In Figure 8, the segmentation profiles of carriers expressing the most common mutations, p.G1961E, p. Login to comment 163 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu [L541P; A1038V], p.P1380L, and p.L2027F, are indicated in color. Login to comment 169 ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Nevertheless, we concluded that based on qAF values (measured at an eccentricity of 78-98), the mutations p.L2027F and p.P1380L and the complex allele p. Login to comment 170 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Gly851Asp [L541P; A1038V] conferred a faster rate of lipofuscin accumulation, whereas accumulation in the presence of the p.G1961E and p.G851D mutations was slower. Login to comment 185 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Several years ago a case-control study of unrelated subjects with AMD identified heterozygous ABCA4 mutations in a subgroup of AMD cases; six of these patients harbored the p.G1961E mutation.18 A follow-up study detected the p.G1961E variant statistically significantly more frequently in AMD cases than in matched controls.36 The p.G1961E mutation is exceptional in that STGD1 patients homozygous for the mutation or compound FIGURE 7. Login to comment 191 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu heterozygous for p.G1961E and another disease-associated allele exhibit qAF levels (measured 78-98 from fovea) that are either within the normal range or modestly higher (Fig. 4).24 These observations with respect to G1961E are consistent with an earlier study wherein most patients with this mutation did not present with a dark choroid during fundus angiography.37 The dark choroid is thought to be conferred by high lipofuscin levels. Login to comment 192 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Thus since STGD1 patients expressing the G1961E mutation have relatively normal qAF intensities, the finding that carriers of a G1961E mutation also do not exhibit elevated qAF is not informative with respect to the burden of disease. Login to comment 196 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Thickness profiles acquired by segmentation of spectral-domain optical coherence tomography (SD-OCT) images of carriers of ABCA4 mutations p.G1961E, p.L541P/A1038V, p.P1380L, and p.L2027F. Login to comment 205 ABCA4 p.Val2050Leu Heterozygous mutations in ABCA4 (p.V2050L) have also been reported to contribute to an exacerbation of the phenotype conferred by a monoallelic mutation in PRPH2 (p.R172W).41 In another study, 12 nonsymptomatic mutation-carrying relatives of STGD1 patients were found to have normal visual acuity but impaired contrast sensitivity and reduced multifocal ERG amplitudes.21 More recently, a subset of ABCA4 carriers were reported to have reduced visual acuity, fundus abnormalities that included pigmentary changes (8/18) and flecks, and multifocal ERGs of reduced amplitude and delayed implicit times.22 Some missense mutations, including the complex allele p. Login to comment 206 ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro [L541P;A1038V], have been shown to be associated with ABCA4 mislocalization; the p.L541P mutation in particular prevents correct localization of ABCA4 in OS and thus retention in inner segments.42 It is expected that under these conditions the pathogenesis of STGD1 could be exacerbated by endoplasmic reticulum (ER) stress and the unfolded-protein response (UPR).43 Since the onset of the UPR may be dependent on mutation type and gene dosage, a monoallelic p. Login to comment 207 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro [L541P; A1038V] mutation may leave photoreceptor cells with a limited and latent capacity to deal with other sources of ER stress. Login to comment 298 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Zhang R, Wang LY, Wang YF, et al. Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration. Login to comment