ABCMdb

ABCA4 p.Gly607Arg

ClinVar:	c.1819G>T , p.Gly607Trp ? , not provided c.1819G>A , p.Gly607Arg ? , not provided
Predicted by SNAP2:	A: D (63%), C: D (71%), D: D (71%), E: D (71%), F: D (85%), H: D (66%), I: D (80%), K: D (66%), L: D (85%), M: D (80%), N: D (53%), P: D (71%), Q: D (66%), R: D (91%), S: D (53%), T: D (59%), V: D (75%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] The ABCA4 gene in autosomal recessive cone-rod dys... Am J Hum Genet. 2002 Dec;71(6):1480-2. Ducroq D, Rozet JM, Gerber S, Perrault I, Barbet D, Hanein S, Hakiki S, Dufier JL, Munnich A, Hamel C, Kaplan J
The ABCA4 gene in autosomal recessive cone-rod dystrophies.
Am J Hum Genet. 2002 Dec;71(6):1480-2., [PMID:12515255]

Abstract [show]

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
30 Among these 13 patients, 2 were homozygotes (from two consanguineous families), 4 were compound heterozygotes, and 7 were Letters to the Editor 1481 Table 1 ABCA4 Mutations in Patients with CRD Patient ABCA4 ALLELE 1 ABCA4 ALLELE 2 OriginNucleotide Change Effect Nucleotide Change Effect 16 AAC 286 GAC N96D - - France 52 ATC 466 GTC I156V - - North Africa 57 ATC 466 GTC I156V GGG 1819 AGG G607R North Africa 51 CGA 455 CAA 5084ϩ1G/A R152Q Frameshift CGC 3323 TGC AGT 6764 ATT R1108C S2256I France 11 CGT 764 TGT R255C - - France 41 GCC 3113 GTC A1038V - - France 60 CTG 3602 CGG L1201R AGT 6764 ATT S2256I South Africa 21 CTC 5908 TTC L1970F - - France 30 AGT 6764 ATT S2256I - - Africa 48 GAA 3259 TAA E1087X - - France 2 2617 del CT Frameshift 2617 del CT Frameshift Portugal 5 571-2A/G Frameshift 571-2A/G Frameshift Morocco 61 CGG 4918 TGG R1602W GGC 5929 AGC G1977S England single heterozygotes (see table 1). Login to comment
31 Among these 13 patients, 2 were homozygotes (from two consanguineous families), 4 were compound heterozygotes, and 7 were Letters to the Editor 1481 Table 1 ABCA4 Mutations in Patients with CRD Patient ABCA4 ALLELE 1 ABCA4 ALLELE 2 Origin Nucleotide Change Effect Nucleotide Change Effect 16 AAC 286 GAC N96D - - France 52 ATC 466 GTC I156V - - North Africa 57 ATC 466 GTC I156V GGG 1819 AGG G607R North Africa 51 CGA 455 CAA 5084af9;1G/A R152Q Frameshift CGC 3323 TGC AGT 6764 ATT R1108C S2256I France 11 CGT 764 TGT R255C - - France 41 GCC 3113 GTC A1038V - - France 60 CTG 3602 CGG L1201R AGT 6764 ATT S2256I South Africa 21 CTC 5908 TTC L1970F - - France 30 AGT 6764 ATT S2256I - - Africa 48 GAA 3259 TAA E1087X - - France 2 2617 del CT Frameshift 2617 del CT Frameshift Portugal 5 571-2A/G Frameshift 571-2A/G Frameshift Morocco 61 CGG 4918 TGG R1602W GGC 5929 AGC G1977S England single heterozygotes (see table 1). Login to comment

[hide] Alterations of slow and fast rod ERG signals in pa... Invest Ophthalmol Vis Sci. 2002 Apr;43(4):1248-56. Scholl HP, Besch D, Vonthein R, Weber BH, Apfelstedt-Sylla E
Alterations of slow and fast rod ERG signals in patients with molecularly confirmed Stargardt disease type 1.
Invest Ophthalmol Vis Sci. 2002 Apr;43(4):1248-56., [PMID:11923272]

Abstract [show]
PURPOSE: To investigate the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients with molecularly confirmed Stargardt disease type I (STGD1). There is evidence that these slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone coupling pathway, respectively. METHODS: Twenty-seven patients with STGD1 with mutations in both alleles of the ABCA4 gene were included. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic troland x sec (log scot td x sec) were measured at a flicker frequency of 15 Hz. In addition, scotopic standard ERGs were obtained. Twenty-two normal subjects served as controls. RESULTS: The amplitudes of both the slow and fast rod ERG signals were significantly reduced in the STGD1 group. The phases of the slow rod signals lagged significantly, whereas those of the fast rod signals did not. The standard scotopic ERG did not reveal significant alterations. CONCLUSIONS: The results provide evidence that a defective ABCA4 transporter can functionally affect both the rod bipolar-AII cell pathway and the rod-cone coupling pathway. In STGD1, the scotopic 15-Hz flicker ERG may reveal subtle abnormalities at different sites within the rod system that remain undetected by standard ERG techniques.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
97 Characteristics of the 27 patients with STGD1 Patient Sex Age Onset VA (OD) VA (OS) CFC DF Mut(1) Mut(2) Slow Rod ERG Fast Rod ERG 1 M 32 9 1/50 20/400 Severe ϩϩ Q1412X R2077W 19.2 12.1 2 M 49 17 20/200 20/200 Severe ϩ 768G3T G1961E 56.1 23.8 3 M 46 30 20/40 20/200 Mild ϩ E471K G1961E 31.7 29.0 4* M 27 19 20/32 20/100 Moderate ϩ 2588G3C E1885K 35.0 45.1 5* M 31 18 20/400 20/400 Severe ϩϩ 2588G3C E1885K 36.1 39.1 6* F 29 12 20/200 20/200 Moderate ϩϩ 2588G3C E1885K 23.4 8.1 7 F 23 18 20/400 20/400 Mild ϩϩ E1399K G1977S 103.5 39.3 8 M 28 17 20/200 20/200 Mild ϩϩ R1898H G1975R 44.4 19.5 9 M 39 29 20/100 20/200 Moderate ϩ G607R G1961E 45.8 20.7 10 F 23 17 20/200 20/200 Mild - P68L S1689P 80.2 25.9 11 F 33 30 20/50 20/50 Mild - E1399K G1961E 49.8 62.0 12 M 50 42 20/400 20/64 Severe ϩϩ 2588G3C L541P/A1038V 53.8 30.2 13 M 36 25 20/40 20/32 Moderate ϩϩ 296insA A1038V 88.2 40.0 14 F 55 16 HM HM Severe ϩϩ Q635K IVS40ϩ5G3A 11.7 11.2 15 F 27 25 20/100 20/50 Moderate ϩ 2588G3C Q1412X 65.8 71.5 16 F 45 14 1/50 1/35 Severe ϩϩ L541P/A1038V S1063P 16.4 16.6 17 M 40 23 20/100 20/200 Moderate ϩ 296insA G1961E 46.1 58.3 18** M 35 15 20/400 20/400 Moderate ϩ 2588G3C Q1750X 14.1 12.9 19** M 43 14 HM HM Severe ϩϩ 2588G3C Q1750X 17.4 8.6 20 F 32 8 20/200 20/200 Severe ϩ G1961E G1961E 66.2 79.0 21 F 23 12 20/400 20/400 Mild - R212C T9591 24.6 25.3 22 F 29 9 20/200 20/200 Moderate ϩ L541P/A1038V G1961E 72.3 31.8 23 M 20 9 20/400 20/400 Moderate ϩϩ L541P/A1038V IVS40ϩ5G3A 64.7 42.2 24 F 39 23 20/400 20/50 Moderate - W663X G1961E 92.6 68.8 25 F 41 36 20/200 20/64 Severe ϩ F1440V G1748R 97.2 52.7 26*** M 13 10 20/100 20/200 Moderate - R572Q/2588G3C IVS35ϩ2T3A 59.2 33.5 27*** M 16 15 20/200 20/200 Moderate ϩ R572Q/2588G3C IVS35ϩ2T3A 31.1 22.9 Age at examination (y), gender, age of onset (y), visual acuity (VA), central fundus changes (CFC), and existence and distribution of the typical white-yellow flecks (DF) are shown. Login to comment

[hide] L- and M-cone-driven electroretinograms in Stargar... Invest Ophthalmol Vis Sci. 2001 May;42(6):1380-9. Scholl HP, Kremers J, Vonthein R, White K, Weber BH
L- and M-cone-driven electroretinograms in Stargardt's macular dystrophy-fundus flavimaculatus.
Invest Ophthalmol Vis Sci. 2001 May;42(6):1380-9., [PMID:11328755]

Abstract [show]
PURPOSE: To study the dynamics of the long (L)- and middle (M)-wavelength-sensitive cone-driven pathways and their interactions in patients with Stargardt's macular dystrophy-fundus flavimaculatus (SMD-FF) and to correlate them with other clinical parameters and individual genotypes. METHODS: Forty-seven patients with SMD-FF participated in the study. In addition to standard 30-Hz flicker electroretinograms (30-Hz fERG), ERG responses were measured to stimuli that modulated exclusively the L or the M cones (L/M cones) or the two simultaneously. Blood samples were screened for mutations in the 50 exons of the ABCA4 gene. RESULTS: Patients with SMD-FF did not show a decrease in the mean L/M-cone-driven ERG sensitivity, but there was a significant increase in the interindividual variability. The mean L-/M-cone weighting ratio was normal. However, the L-cone-driven ERG was significantly phase delayed, whereas the M-cone-driven ERG was significantly phase advanced. These phase changes were significantly correlated with disease duration. The amplitude and implicit time of the standard 30-Hz fERG both correlated significantly with the L/M-cone-driven ERG sensitivity and with the phase difference between the L/M-cone-driven ERGs, indicating the complex origin of the standard 30-Hz fERG. Probable disease-associated mutations in the ABCA4 gene were found in 40 of 45 patients, suggesting that they form a genetically fairly uniform SMD-FF study group. There was no correlation between the genotype and the L/M-cone-driven ERGS: CONCLUSIONS: The changes in L/M-cone-driven ERG sensitivity and phase possibly represent two independent disease processes. The phase changes are similar to those found in patients with retinitis pigmentosa and possibly are a general feature of retinal dystrophies.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
43 Characteristics of the Patients with SMD-FF Patient Sex Age (y) Age at Onset (y) VA CFC DF CV Exon (1) Mut (1) Exon (2) Mut (2) 1 M 32 29 0.6 Moderate ϩ Normal 48 L2241V NF 2 F 39 23 0.4 Moderate - Chaotic 14 W663X 42 G1961E 3 M 34 16 0.1 Moderate ϩ - 42 G1961E NF 4 M 49 17 0.1 Severe ϩ NP 6 G768T/splice 42 G1961E 5 F 36 35 0.6 Moderate ϩ VS (T) 6 C230S 42 G1961E 6 M 28 17 0.1 Mild ϩϩ INS 40 R1898H 43 G1975R 7 M 20 9 0.05 Moderate ϩϩ VS (P/D) 12 ϩ 21 L541P ϩ A1038V 40 IVS40 ϩ 5G 3 A 8 M 33 6 0.1 Mild - Chaotic NF NF 9 M 39 29 0.2 Moderate ϩ VS (P/D) 13 G607R 42 G1961E 10 M 38 22 0.1 Severe ϩ Chaotic NF NF 11 F 28 20 0.7 Mild ϩϩ INS 3 A60T 40 R1898H 12 M 46 30 0.5 Mild ϩ Chaotic 11 E471K 42 G1961E 13 F 25 11 0.1 Moderate ϩϩ S 17 G863A NF 14 F 51 41 0.8 Moderate ϩϩ NP 40 R1898H NF 15 F 23 17 0.1 Mild - Chaotic 3 P68L 36 S1689P 16 F 33 30 0.4 Mild - Chaotic 28 E1399K 42 G1961E 17 F 41 36 0.1 Severe ϩ VS (T) 29 F1440V 37 G1748R 18 M 59 54 0.1 Severe ϩ VS (P/D) 42 G1961E NF 19* M 35 15 0.05 Moderate ϩ Chaotic 17 G863A 37 Q1750X 20* M 43 14 HM Severe ϩϩ NP 17 G863A 37 Q1750X 21 F 46 16 0.1 Moderate ϩ NP NF NF 22 F 32 22 0.05 Moderate ϩ INS 21 A1038V NF 23 M 50 42 0.3 Severe ϩϩ VS (P/D) 12 ϩ 21 L541P ϩ A1038V 17 G863A 24 F 30 14 0.1 Moderate ϩϩ INS 17 G863A 40 IVS40 ϩ 5G 3 A 25 M 36 25 0.5 Moderate ϩϩ - 3 296INSA 21 A1038V 26 M 40 23 0.2 Moderate ϩ S 3 296INSA 42 G1961E 27 F 35 9 0.1 Severe ϩϩ VS (P/D) 22 R1108C NF 28 F 23 18 0.05 Mild ϩϩ S 28 E1399K 43 G1977S 29 F 25 18 0.2 Mild ϩ Chaotic 37 L1763P NF 30 F 16 11 0.1 Moderate ϩ Chaotic 22 R1108C NF 31 M 40 35 0.1 Moderate ϩϩ VS (P/D) 14 R681X NF 32 F 28 27 0.1 Moderate ϩ S 12 ϩ 21 L541P ϩ A1038V 21 A1038V 33 M 32 9 0.05 Severe ϩϩ Chaotic 28 Q1412X 45 R2077W 34 F 23 21 0.2 Moderate ϩ INS 6 G768T/splice NF 35 F 38 33 FC Moderate - Chaotic 17 G863A NF 36 F 39 10 HM Severe ϩϩ NP NF NF 37 F 13 8 0.1 Moderate ϩϩ S - - 38 F 27 25 0.2 Moderate ϩ Chaotic 17 G863A 28 Q1412X 39 M 16 15 0.1 Moderate ϩ VS (P/D) 12 ϩ 17 R572Q ϩ G863A 35 IVS35 ϩ 2T 3 A 40 M 27 26 0.6 Moderate - S 17 G863A NF 41 M 18 16 0.2 Moderate ϩ - - - 42 M 25 24 0.1 Mild - - NF NF 43 F 29 9 0.1 Moderate ϩ Chaotic 12 ϩ 21 L541P ϩ A1038V 42 G1961E 44 M 39 28 0.1 Mild - NP 6 N247S NF 45 F 23 12 0.05 Mild - NP 6 R212C 19 T959I 46 M 43 36 0.2 Moderate ϩ VS (P/D) 21 A1038V NF 47 M 21 18 0.4 Mild ϩϩ INS 28 Q1412X NF Shown are age at examination, age of onset, visual acuity, central fundus changes, and existence and distribution of the typical white-yellow flecks. Login to comment
44 Characteristics of the Patients with SMD-FF Patient Sex Age (y) Age at Onset (y) VA CFC DF CV Exon (1) Mut (1) Exon (2) Mut (2) 1 M 32 29 0.6 Moderate af9; Normal 48 L2241V NF 2 F 39 23 0.4 Moderate afa; Chaotic 14 W663X 42 G1961E 3 M 34 16 0.1 Moderate af9; - 42 G1961E NF 4 M 49 17 0.1 Severe af9; NP 6 G768T/splice 42 G1961E 5 F 36 35 0.6 Moderate af9; VS (T) 6 C230S 42 G1961E 6 M 28 17 0.1 Mild af9;af9; INS 40 R1898H 43 G1975R 7 M 20 9 0.05 Moderate af9;af9; VS (P/D) 12 af9; 21 L541P af9; A1038V 40 IVS40 af9; 5G 3 A 8 M 33 6 0.1 Mild afa; Chaotic NF NF 9 M 39 29 0.2 Moderate af9; VS (P/D) 13 G607R 42 G1961E 10 M 38 22 0.1 Severe af9; Chaotic NF NF 11 F 28 20 0.7 Mild af9;af9; INS 3 A60T 40 R1898H 12 M 46 30 0.5 Mild af9; Chaotic 11 E471K 42 G1961E 13 F 25 11 0.1 Moderate af9;af9; S 17 G863A NF 14 F 51 41 0.8 Moderate af9;af9; NP 40 R1898H NF 15 F 23 17 0.1 Mild afa; Chaotic 3 P68L 36 S1689P 16 F 33 30 0.4 Mild afa; Chaotic 28 E1399K 42 G1961E 17 F 41 36 0.1 Severe af9; VS (T) 29 F1440V 37 G1748R 18 M 59 54 0.1 Severe af9; VS (P/D) 42 G1961E NF 19* M 35 15 0.05 Moderate af9; Chaotic 17 G863A 37 Q1750X 20* M 43 14 HM Severe af9;af9; NP 17 G863A 37 Q1750X 21 F 46 16 0.1 Moderate af9; NP NF NF 22 F 32 22 0.05 Moderate af9; INS 21 A1038V NF 23 M 50 42 0.3 Severe af9;af9; VS (P/D) 12 af9; 21 L541P af9; A1038V 17 G863A 24 F 30 14 0.1 Moderate af9;af9; INS 17 G863A 40 IVS40 af9; 5G 3 A 25 M 36 25 0.5 Moderate af9;af9; - 3 296INSA 21 A1038V 26 M 40 23 0.2 Moderate af9; S 3 296INSA 42 G1961E 27 F 35 9 0.1 Severe af9;af9; VS (P/D) 22 R1108C NF 28 F 23 18 0.05 Mild af9;af9; S 28 E1399K 43 G1977S 29 F 25 18 0.2 Mild af9; Chaotic 37 L1763P NF 30 F 16 11 0.1 Moderate af9; Chaotic 22 R1108C NF 31 M 40 35 0.1 Moderate af9;af9; VS (P/D) 14 R681X NF 32 F 28 27 0.1 Moderate af9; S 12 af9; 21 L541P af9; A1038V 21 A1038V 33 M 32 9 0.05 Severe af9;af9; Chaotic 28 Q1412X 45 R2077W 34 F 23 21 0.2 Moderate af9; INS 6 G768T/splice NF 35 F 38 33 FC Moderate afa; Chaotic 17 G863A NF 36 F 39 10 HM Severe af9;af9; NP NF NF 37 F 13 8 0.1 Moderate af9;af9; S - - 38 F 27 25 0.2 Moderate af9; Chaotic 17 G863A 28 Q1412X 39 M 16 15 0.1 Moderate af9; VS (P/D) 12 af9; 17 R572Q af9; G863A 35 IVS35 af9; 2T 3 A 40 M 27 26 0.6 Moderate afa; S 17 G863A NF 41 M 18 16 0.2 Moderate af9; - - - 42 M 25 24 0.1 Mild afa; - NF NF 43 F 29 9 0.1 Moderate af9; Chaotic 12 af9; 21 L541P af9; A1038V 42 G1961E 44 M 39 28 0.1 Mild afa; NP 6 N247S NF 45 F 23 12 0.05 Mild afa; NP 6 R212C 19 T959I 46 M 43 36 0.2 Moderate af9; VS (P/D) 21 A1038V NF 47 M 21 18 0.4 Mild af9;af9; INS 28 Q1412X NF Shown are age at examination, age of onset, visual acuity, central fundus changes, and existence and distribution of the typical white-yellow flecks. 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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
80 Nucleotide alterations occurring in sim- Table 2 ABCA4 Mutations Found in Patients with STGD and AMD and in Controls EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (288) AMD (400) Control (440) 3: 178GrA A60T 1 0 0 This study 179CrT A60E 1 0 0 This study 194GrA G65E 1 0 0 Fishman et al. (1999) 203CrT P68L 1 0 0 This study 214GrA G72R 1 0 0 This study 296insA Frameshift 2 0 0 This study 5: 454CrT R152X 1 0 0 This study 6: 634CrT R212C 1 0 0 Lewis et al. (1999) 688TrA C230S 1 0 0 This study 730delCT Frameshift 1 0 0 This study 740ArG N247S 1 0 0 This study 768GrT Splice 2 0 0 Maugeri et al. (1999) 8: 983ArT E328V 1a 0 0 This study 1086TrA Y362X 1 0 0 This study 10: 1317GrA W438X 1 0 0 This study 11: 1411GrA E471K 1 0 0 Lewis et al. (1999) 12: 1622TrC L541P 21a 1a 0 Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) 1715GrA R572Q 1a 0 0 Lewis et al. (1999) 13: 1819GrA G607R 1 0 0 This study 1903CrA Q635K 2a 0 0 This study 1903CrT Q635X 1 0 0 This study IVS13ϩ1GrA Splice 2 0 0 This study 14: 1957CrT R653C 1 0 0 This study 1988GrA W663X 1 0 0 This study 2041CrT R681X 4 0 0 Maugeri et al. (1999) 15: 2291GrA C764Y 1 0 0 This study 2292delT Frameshift 1a 0 0 This study 2295TrG S765R 1a 0 0 This study 16: 2564GrA W855X 1 0 0 Nasonkin et al. (1998) 17: 2588GrC Spliceb 17a 6 5 Allikmets et al. (1997a), Cremers et al. (1998), Lewis et al. (1999), Maugeri et al. (1999), Papaioannou et al. (2000) 18: 2701ArG T901A 0 2 0 This study 2741ArG H914A 0 0 1 This study 19: 2876CrT T959I 1 0 0 This study 20: IVS20ϩ5GrA Splice 1 0 0 This study 21: 3106GrA E1036K 1a 0 0 Nasonkin et al. (1998) 3113CrT A1038V 26a 4a 1 Allikmets et al. (1997a), Cremers et al. (1998), Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) T3187TrC S1063P 1 0 0 This study (Continued) 805 Table 2 Continued EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (288) AMD (400) Control (440) 22: 3292CrT R1097C 1 0 0 This study 3322CrT R1108C 4 0 0 Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999) 24: 3528insTGCA Frameshift 1 0 0 This study 25: 3808GrT E1270X 1 0 0 This study 27: 3898CrT R1300X 1 0 0 This study 28: IVS28ϩ5GrA Splice 1 0 0 This study 4139CrT P1380L 1 0 0 Lewis et al. (1999) 4195GrA E1399K 2 0 0 This study 4234CrT Q1412X 4 0 0 Maugeri et al. (1999) 29: 4289TrC L1430P 2 0 0 This study 4318TrG F1440V 1 0 0 This study 4328GrA R1443H 1 0 0 This study 30: 4457CrT P1486L 1 0 0 Lewis et al. (1999) 4463GrA C1488Y 1 0 0 This study 31: 4610CrT T1537M 1 0 0 This study 35: IVS35ϩ2TrA Splice 1 0 0 This study 36: 5065TrC S1689P 1 0 0 This study 5114GrT R1705L 1 0 0 This study IVS36ϩ1GrA Splice 1 0 0 This study 37: 5198TrC M1733T 0 0 1 This study 5242GrA G1748R 1 0 0 This study 5248CrT Q1750X 1 0 0 This study 5288TrC L1763P 1 0 0 This study 38: IVS38ϩ1GrA Splice 1 0 0 This study 40: 5653GrA E1885K 1 0 0 This study 5693GrA R1898H 5 2 1 Allikmets et al. (1997b), Lewis et al. (1999) IVS40ϩ5GrA Splice 8a 0 0 Cremers et al. (1998), Lewis et al. (1999), Maugeri et al. (1999) 42: 5882GrA G1961E 34 4 2 Allikmets et al. (1997b), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) 43: 5917delG Frameshift 3 0 0 This study 5923GrC G1975R 1 0 0 This study 5929GrA G1977S 1 0 0 Rozet et al. (1998), Lewis et al. (1999) 45: 6229CrG R2077G 1 0 0 This study 6229CrT R2077W 1 0 0 Allikmets et al. (1997a), Fishman et al. (1999), Lewis et al. (1999) 48: 6609CrA Y2203X 2 0 0 This study 6647GrT A2216V 0 0 1 This study a Mutation pairs occurring on a single haplotype. Login to comment
111 Likewise, for the intron 28 alteration, a spliced product Table 5 Patients with STGD Who Have Two Identified Disease Alleles AGE AT ONSET AND PATIENT MUTATION SEGREGATION IN FAMILY a Allele 1 Allele 2 5-9 years: STGD17 Q1412X R2077W Yes STGD88 G65E G1961E NA STGD93 G1961E G1961E Yes STGD99 L541P-A1038V G1961E Yes STGD100 L541P-A1038V IVS40ϩ5GrA Yes STGD108 Y362X IVS40ϩ5GrA Yes STGD109 L541P-A1038V W855X Yes STGD139b 5917delG 5917delG Yes STGD167 C1488Y IVS40ϩ5GrA Yes 10-14 years: STGD21 R681X R1898H NA STGD37 L541P-A1038V L541P-A1038V Yes STGD47/164 IVS13ϩ1GrA 2588GrC Yes STGD50 2588GrC A1038V NA STGD70 2588GrC IVS40ϩ5GrA NA STGD82 L541P-A1038V S1063P Yes STGD87 2588GrC Q1750X Yes STGD98 R212C T959I Yes STGD102 R572Q-2588GrC IVS35ϩ2TrA Yes STGD107 C764Y 3528ins4 Yes STGD120 L1430P L1430P NA STGD121 R1300X IVS40ϩ5GrA Yes STGD156 R1108C G1961E NA STGD159 R1108C Q1412X Yes STGD171 L541P-A1038V G1961E NA 15-19 years: STGD34 G768T G1961E Yes STGD39 L541P-A1038V R1443H NA STGD40/163 2588GrC E1885K Yes STGD45 E1399K G1977S Yes STGD59 R1898H G1975R NA STGD67 P68L S1689P Yes STGD75 Q635K IVS40ϩ5GrA Yes STGD111 2292delT-S765R G1961E Yes STGD114 Y2203X G1961E Yes STGD138 IVS13ϩ1GA 2588GrC Yes 20-24 years: STGD41 R681X G1961E Yes STGD63 A60T R1898H NA STGD86 296insA G1961E Yes STGD91 L541P-A1038V A1038V NA STGD113 L541P-A1038V 2588GrC Yes STGD118b IVS20ϩ5GrA G1961E Yes STGD119 L541P-A1038V G1961E Yes STGD122 L541P-A1038V G1961E Yes STGD135 W663X G1961E NA STGD147 IVS36ϩ1GrA G1961E Yes STGD168 L541P-A1038V G1961E NA 25-29 years: STGD62 G607R G1961E NA STGD71 296insA A1038V Yes STGD78 2588GrC Q1412X Yes STGD103 2588GrC IVS20ϩ5GrA Yes STGD116 L541P-A1038V G1961E Yes STGD139bb G1961E 5917delG Yes у30 years: STGD38 E471K G1961E Yes STGD68 E1399K G1961E Yes STGD69 L541P-A1038V 2588GrC NA STGD95 F1440V G1748R Yes STGD134 C230S G1961E NA STGD144 2588GrC R1705L NA STGD148 R1097C Y2203X NA STGD170 L541P-A1038V 2588GrC NA a NA p not applicable. Login to comment

[hide] Exome sequencing analysis identifies compound hete... PLoS One. 2014 Mar 14;9(3):e91962. doi: 10.1371/journal.pone.0091962. eCollection 2014. Zhou Y, Tao S, Chen H, Huang L, Zhu X, Li Y, Wang Z, Lin H, Hao F, Yang Z, Wang L, Zhu X
Exome sequencing analysis identifies compound heterozygous mutation in ABCA4 in a Chinese family with Stargardt disease.
PLoS One. 2014 Mar 14;9(3):e91962. doi: 10.1371/journal.pone.0091962. eCollection 2014., [PMID:24632595]

Abstract [show]
Stargardt disease is the most common cause of juvenile macular dystrophy. Five subjects from a two-generation Chinese family with Stargardt disease are reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family initiated the disease during childhood, developing progressively impaired central vision and bilateral atrophic macular lesions in the retinal pigmental epithelium (RPE) that resembled a "beaten-bronze" appearance. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. Exome sequencing was used to analyze the exome of two patients II1, II2. A total of 50709 variations shared by the two patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in all family members by PCR and Sanger sequencing. Compound heterozygous variants p.Y808X and p.G607R of the ATP-binding cassette, sub-family A (ABC1), member 4 (ABCA4) gene, which encodes the ABCA4 protein, a member of the ATP-binding cassette (ABC) transport superfamily, were identified as causative mutations for Stargardt disease of this family. Our findings provide one novel ABCA4 mutation in Chinese patients with Stargardt disease.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
8 Compound heterozygous variants p.Y808X and p.G607R of the ATP-binding cassette, sub-family A (ABC1), member 4 (ABCA4) gene, which encodes the ABCA4 protein, a member of the ATP-binding cassette (ABC) transport superfamily, were identified as causative mutations for Stargardt disease of this family. Login to comment
39 Our results identified two compound heterozygous disease-segregating mutations, c.C2424G, p.Y808X and c.G1819A, p.G607R, in the ABCA4 gene. Login to comment
67 Family Member Age Gender Disease Duration (years) Visual Acuity (OD, OS) Mutation(s) Original reports described Nucleotide change Effect I1 43 M 0 20/20, 20/20 1819G.A Gly 607 Arg Andrea Rivera I2 43 F 0 20/20, 20/20 2424C.G Tyr 808* N/A II1 13 M 3 20/400, 20/400 1819G.A/2424C.G Gly 607 Arg,/Tyr 808* Andrea Rivera,N/A II2 18 F 8 20/400, 20/400 1819G.A/2424C.G Gly 607 Arg,/Tyr 808* Andrea Rivera,N/A II3 20 F 0 20/20, 20/20 1819G.A Gly 607 Arg Andrea Rivera N/A, Not available; M, Male; F, Female. Login to comment
109 In both patients we found two mutations c.C2424G (p.Y808X) and c.G1819A (p.G607R) satisfying a recessive compound heterozygous inheritance model (Table 3) in the gene ABCA4 (NM_000350.2). Login to comment
110 When we checked the human gene mutation database (http://www.hgmd.org/), we found that mutation p.G607R was reported by Andrea Rivera in 2000 [24]. Login to comment
111 Sanger sequencing confirmed these two mutations in the two affected siblings and demonstrated that their parents were unaffected carriers of Y808X (father) and G607R (mother) mutations, showing complete co-segregation of the mutations with the disease phenotype (Figure 3). Login to comment
113 These data, together with the clinical presentation of the two affected siblings, demonstrated that p.G607R and p.Y808X variants in the gene ABCA4 was responsible for Stargardt disease in this family. Login to comment
115 The previously reported mutation p.G607R of ABCA4 was predicted to be damaging and the novel mutation c.C2424G, p.Y808X in the affected families introduced a stop codon, which removed 1465 amino acids from the ABCA4 protein (2273 amino acids), according to GenBank accession number NM_000350.2. Login to comment
118 Mutation p.G607R, located within exon 13, results in changes of a hydrophilic glycine to an arginine at position 607, which may lead to a damaging replacement with a score of 0.99 (sensitivity:0.72, specificity:0.97) Figure 4A. Login to comment
131 Our result also indicated that G607R occurs in the ECD1 domain, while Y808X occurs in the disc lumen region between TMD1 (Figure 4B). Login to comment
146 (A) Protein alignment showed conservation of residues ABCA4 Y808X and G607R across nine species. Login to comment
148 The ABCA4 mutation G607R occured in the NBD1 while Y808X occured in the disc lumen region between TMD1. Login to comment
157 In our study compound heterozygous mutations p.Y808X and p.G607R of the ABCA4 gene were identified. Login to comment
158 The previously reported ABCA4 p.G607R mutation [24,50] in exon 13 is a single nucleotide polymorphism, rs61749412, which is predicted probably to be damaging to protein function (PolyPhen2 scores close to 1.0). Login to comment
159 Through the analysis of membrane topology by TMHMM2.0, we found that the p.G607R mutation was in the ABCA4 ECD1 region, which is involved in stacking interactions with the adenine ring of ATP [51]. Login to comment

[hide] Clinical and molecular genetic study of 12 Italian... Genet Mol Res. 2012 Dec 17;11(4):4342-50. doi: 10.4238/2012.October.9.3. Oldani M, Marchi S, Giani A, Cecchin S, Rigoni E, Persi A, Podavini D, Guerrini A, Nervegna A, Staurenghi G, Bertelli M
Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease.
Genet Mol Res. 2012 Dec 17;11(4):4342-50. doi: 10.4238/2012.October.9.3., [PMID:23096905]

Abstract [show]
Stargardt disease was diagnosed in 12 patients from 12 families using complete ophthalmologic examination, fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. DNA was extracted for polymerase chain reaction (PCR) and direct DNA sequencing (ABCA4 gene). Genetic counseling and eye examination were offered to 16 additional family members. Various patterns of presentation were observed in patients with clinical diagnoses of Stargardt disease. The genetic study identified 2 mutations in 75% of families (9/12); a second mutation could not be found in the remaining 25% of families (3/12). The most frequent mutation was G1961E, found in 17% of families (2/12). This finding is similar to that of a previous analysis report of an Italian patient series. Four new mutations were also identified: Tyr1858Asp, Leu1195fsX1196, p.Tyr850Cys, and p.Thr959Ala. Our results suggest that PCR and direct DNA sequencing are the most appropriate techniques for the analysis of the ABCA4 gene. However, this method requires supplementation with specific PCR analysis to diagnose large deletions. The study of the families identified healthy carriers and affected subjects in presymptomatic stages and was also useful for evaluating the risk of transmission to progeny. Combined ophthalmologic and genetic evaluation enabled better clinical management of these families.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
69 of patients Subject Allele 1 Allele 2 Age of diagnosis (years) Visual acuity Right eye Left eye 1 F1 ID81 Tyr1858Asp Met1Val; Arg2030Gln 22 20/50 20/32 2 F2 ID220 Ile156Val Gly607Arg; Gly1961Glu 30 20/800 20/400 3 F3 ID362 Met1Val Gly1961Glu; Arg2030Gln 60 20/40 20/32 4 F4 ID197 Asp1532Asn Arg2030term 40 20/32 20/32 5 F6 ID363 Tyr362Term Gly863Ala 16 20/200 20/250 6 F7 ID365 Arg1098Cys Cys1488Arg 50 20/32 20/800 7 F8 ID394 Arg18Trp Val767Asp 10 20/800 20/800 8 F9 ID396 IVS40+5G>A IVS13+1G>A 19 20/40 20/50 9 F10 ID366 p.Gln1513Profs*42 - 20 20/200 20/200 10 F12 ID377 Leu1195Argfs*2 - 50 20/32 20/20 11 F13 ID4 Cys2150Tyr - 70 20/400 20/400 12 F17 ID457 p.Tyr850Cys p.Thr959Ala 50 20/20 20/40 F1 = family 1; ID = reference code to a specific patient. Login to comment

[hide] Molecular diagnosis of putative Stargardt disease ... PLoS One. 2014 Apr 24;9(4):e95528. doi: 10.1371/journal.pone.0095528. eCollection 2014. Zhang X, Ge X, Shi W, Huang P, Min Q, Li M, Yu X, Wu Y, Zhao G, Tong Y, Jin ZB, Qu J, Gu F
Molecular diagnosis of putative Stargardt disease by capture next generation sequencing.
PLoS One. 2014 Apr 24;9(4):e95528. doi: 10.1371/journal.pone.0095528. eCollection 2014., [PMID:24763286]

Abstract [show]
Stargardt Disease (STGD) is the commonest genetic form of juvenile or early adult onset macular degeneration, which is a genetically heterogeneous disease. Molecular diagnosis of STGD remains a challenge in a significant proportion of cases. To address this, seven patients from five putative STGD families were recruited. We performed capture next generation sequencing (CNGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Seven disease-causing mutations in ABCA4 and two in PROM1 were identified by CNGS, which provides a confident genetic diagnosis in these five families. We also provided a genetic basis to explain the differences among putative STGD due to various mutations in different genes. Meanwhile, we show for the first time that compound heterozygous mutations in PROM1 gene could cause cone-rod dystrophy. Our findings support the enormous potential of CNGS in putative STGD molecular diagnosis.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
130 Among these four reported mutations, p.A1773V in ABCA4 was reported as one of the founder mutations (up to17%) in Latin American population [18]; p.R2038W mutation in USA, Estonia and South African population; p.R602W mutation in USA, South African population [2,3,19]; G607R in the German population[20]. Login to comment
132 We observed two mutations (p.R2038W and p.G607R) [1,2], which Figure 5. Login to comment
141 We speculate that the p.G607R mutation may have a higher allelic frequency, because the patient from family C has homozygous mutation of p.G607R and the parents come from different regions. Login to comment