ABCMdb

ABCA4 p.Trp663*

ClinVar:

c.1989G>A , p.Trp663* ? , not provided

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[hide] Familial discordance in Stargardt disease. Mol Vis. 2012;18:227-33. Epub 2012 Jan 28. Burke TR, Tsang SH, Zernant J, Smith RT, Allikmets R
Familial discordance in Stargardt disease.
Mol Vis. 2012;18:227-33. Epub 2012 Jan 28., [PMID:22312191]

Abstract [show]
PURPOSE: To report genetic and phenotypic discordance across two generations of a family with autosomal recessive Stargardt disease (STGD1) and to compare pathogenicities of the G1961E and A1038V alleles of the ATP-binding cassette transporter, subfamily A, member 4 (ABCA4) gene. METHODS: Five members of a family with STGD1 (patients 1-4, affected; patient 5, carrier) were included. Clinical assessment was performed together with fundus autofluorescence and spectral domain-optical coherence tomography. Patients were stratified based on the results of electroretinogram testing. Genotyping of the ABCA4 gene was performed with the ABCR500 microarray. RESULTS: STGD1 was diagnosed in the male proband and his female sibling (patients 1 and 2, respectively). Two children of patient 2 (patients 3 and 4) were also affected. Genotyping revealed the W663X stop mutation in all affected patients. Patients 3 and 4, who were compound heterozygous for the G1961E mutation, had earlier ages of onset than patients 1 and 2, who were compound heterozygous for the A1038V mutation. Patient 1 had an age of onset 28 years younger than patient 2, whose delayed onset can be explained by relative foveal sparing, while patient 4 had an age of onset 44 years younger than patient 2. CONCLUSIONS: The G1961E mutation, which has been considered "mild," yields a more severe phenotype in this family than the A1038V mutation, which has been considered "severe." Marked intrasibship discordance in clinical course is described, suggesting an additional role for modifying factors in ABCA4 pleiotropism.

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3 Genotyping revealed the W663X stop mutation in all affected patients. Login to comment
20 The W663X and A1038V mutations were detected in the ABCA4 gene in both patients 1 and 2, the latter having an onset of symptoms at 57 years of age i.e., 28 years later than her brother. Login to comment
22 Patients 3 and 4 inherited the W663X mutation maternally and the G1961E mutation paternally. Login to comment
28 DISCUSSION Both patients 1 and 2 were compound heterozygous for the W663X and A1038V mutations in the ABCA4 gene. Login to comment
29 W663X was previously reported as a disease-causing mutation [9]; it likely results in a completely dysfunctional protein due to the stop codon in the first 1/4 of the gene. A1038V, a missense mutation, is usually reported as a component of the complex allele L541P/A1038V, one of the most commonly detected mutations in the ABCA4 gene. A1038V is also known to be pathogenic without L541P as it has a deleterious effect on ATPase by ABCA4 in vitro [10,11]. Login to comment
32 The G1961E missense mutation, which has a deleterious effect on ABCA4`s ATPase activity, is the most common mutation detected in the ABCA4 gene and has been reported to confer a milder phenotype [11,16,17]. Login to comment
33 All affected patients in this family carried the W663X mutation, and although G1961E is considered a "mild" mutation, both patients with the G1961E mutation had earlier ages of onset than those with A1038V, which is considered "severe." Login to comment
61 Genotyping revealed the W663X stop mutation in all affected patients. Login to comment
19 The W663X and A1038V mutations were detected in the ABCA4 gene in both patients 1 and 2, the latter having an onset of symptoms at 57 years of age i.e., 28 years later than her brother. Login to comment
21 Patients 3 and 4 inherited the W663X mutation maternally and the G1961E mutation paternally. Login to comment
27 DISCUSSION Both patients 1 and 2 were compound heterozygous for the W663X and A1038V mutations in the ABCA4 gene. Login to comment
41 OD OS Patient #, sex Age at onset (years) Age at exam (years) Duration (years) ERG group VA GA area (mm 2 ) % change from baseline VA GA area (mm 2 ) % change from baseline Allele 1 Allele 2 1, M 29 63 34 I 20/125 7.5 20/150 7 W663X A1038V 64 35 20/150 8.1 0.067 20/150 7.3 0.047 65 36 20/150 9 0.186 20/200 7.9 0.139 2, F 57 68 11 I 20/25 0.4 20/40 1.5 W663X A1038V 69 12 20/30 0.5 0.309 20/30 1.7 0.167 3, M 21 41 20 I 20/150 10.8 20/150 5.8 W663X G1961E 4, F 13 39 26 I 20/150 2.2 20/150 6 W663X G1961E 40 27 20/150 2.9 0.183 20/150 7 0.109 5, M - 68 - - 20/20 - 20/20 - WT G1961E Figure 2. Login to comment

[hide] ABCA4 disease progression and a proposed strategy ... Hum Mol Genet. 2009 Mar 1;18(5):931-41. Epub 2008 Dec 12. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K
ABCA4 disease progression and a proposed strategy for gene therapy.
Hum Mol Genet. 2009 Mar 1;18(5):931-41. Epub 2008 Dec 12., [PMID:19074458]

Abstract [show]
Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.

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153 c Nt, amino-terminal domain; ECD-1 and ECD-2, exocytoplasmic domains 1 and 2; NBD-1 and NBD-2, nucleotide binding domains 1 and 2; TM5, TM6, TM7, TM12, within, near or between transmembrane helices 5, 6, 7 and 12. d W41X, R152X, Y245X, Y362X, W663X, M669del2tccAT, R681X and A1739 del11gcTGGGCTGGTGG. retina-wide blindness, the quality of life deteriorates dramatically with loss of mobility and independence. Login to comment

[hide] Quantifying fixation in patients with Stargardt di... Vision Res. 2007 Jul;47(15):2076-85. Epub 2007 Jun 11. Reinhard J, Messias A, Dietz K, Mackeben M, Lakmann R, Scholl HP, Apfelstedt-Sylla E, Weber BH, Seeliger MW, Zrenner E, Trauzettel-Klosinski S
Quantifying fixation in patients with Stargardt disease.
Vision Res. 2007 Jul;47(15):2076-85. Epub 2007 Jun 11., [PMID:17562343]

Abstract [show]
Fixational eye movements in 60 eyes of 30 patients with ABCA4-associated Stargardt disease were recorded by a Scanning Laser Ophthalmoscope (SLO). The results were quantified by two new fixation quality measures expressing the eccentricity of the preferred retinal locus (PRL) non-parametrically, and fixation stability by a dynamic index. 46 eyes (77%) fixated eccentrically; in 32 eyes (70% of the eccentrically fixating eyes) the PRL was located above the central retinal lesion. PRL eccentricity correlated positively with logMAR visual acuity (r=.72; p<.0001) and negatively with fixation stability (r=-.58; p<.0001). Multiple PRL were found only in three eyes.

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186 of PRL ABCA4 allel1 exon mut 1 ABCA4 allel2 exon mut 2 1 m 32 OD 2 0.4 0.0 90.0 211.0 1 48 L2241V n.f. OS 2 0.6 0.0 90.0 181.6 1 2 f 55 OD 29 0.1 9.7 60.3 9874.6 1 - - - - OS 29 0.1 6.8 67.5 68260.1 2 3 f 38 OD 16 0.05 6.4 73.7 4962.8 1 14 W663X 42 G1961E OS 7 0.4 0.0 90.9 143.5 1 4 m 23 OD 7 0.1 5.7 81.8 664.3 1 40 R1898H 43 G1975R OS 6 0.1 7.0 80.6 594.2 1 5 m 16 OD 7 0.05 7.4 81.0 1052.0 1 12+21 L541P+ 40 IVS40+5 OS 7 0.05 5.0 73.3 11500.0 1 A1038V G->A 6 m 34 OD 34 0.1 0.0 76.2 924.2 1 n.f. n.f. OS 34 0.1 0.0 74.3 1106.2 1 7 m 17 OD 11 0.1 3.1 79.1 3517.6 1 - - - - OS 11 0.1 3.6 70.0 2226.1 1 8 m 46 OD 14 0.5 3.6 80.6 3986.2 1 11 E471K 42 G1961E OS 14 0.2 3.7 58.3 40731.5 1 9 f 26 OD 15 0.1 6.0 70.5 3215.2 1 17 G863A n.f. OS 15 0.1 8.5 56.5 14734.9 1 10 f 19 OD 2 0.1 7.9 65.7 3260.0 1 3 P68L 36 S1689P OS 2 0.1 7.0 63.9 2964.8 1 11 f 34 OD 30 0.4 0.0 88.2 234.1 1 28 E1399K 42 G1961E OS 30 0.4 0.0 87.9 350.0 1 12 m 59 OD 5 0.1 5.2 79.2 1715.5 1 42 G1961E n.f. OS 5 0.1 4.4 75.0 3839.5 1 13 m 35 OD 20 0.05 9.7 72.9 8164.8 1 17 G863A 37 Q1750X OS 20 0.05 10.3 64.9 9820.4 1 14 m 43 OD 29 HM 16.0 58.5 18228.0 1 17 G863A 37 Q1750X OS 29 HM 15.6 42.1 14173.5 1 15 f 32 OD 10 0.05 6.5 61.3 10195.5 1 21 A1038V n.f. OS 10 0.05 5.0 56.7 7560.7 1 16 m 46 OD 4 0.05 8.5 51.1 8641.6 1 12+21 L541P+ 17 G863A OS 4 0.3 5.0 51.1 19827.1 1 A1038V 17 m 43 OD 3 0.5 0.0 90.7 190.9 1 - - - - OS 3 0.7 0.0 81.9 402.2 1 18 f 31 OD 27 1/15 9.8 69.3 2268.5 1 22 R1108C n.f. OS 27 0.1 17.2 60.9 4237.0 1 19 f 23 OD 5 0.05 6.0 72.9 3751.2 1 28 E1399K 43 G1977S OS 5 0.05 6.2 74.8 3578.9 1 20 f 16 OD 5 0.1 6.0 75.8 708.0 1 22 R1108C n.f. OS 5 0.1 5.4 82.4 449.6 1 21 m 38 OD 23 0.1 8.2 53.7 53733.8 2 - - - - OS 12 0.1 6.2 60.3 80873.8 2 22 m 40 OD 6 0.05 16.6 60.8 11677.8 1 14 R681X n.f. OS 6 0.1 10.0 60.6 5134.5 1 23 f 24 OD 3 0.1 6.7 90.5 577.8 1 6 G768T/ n.f. OS 3 0.1 7.1 83.6 3015.2 1 splice 24 m 13 OD 3 0.05 6.9 65.2 1882.7 1 - - - - OS 3 0.05 7.3 53.7 3844.3 1 25 f 39 OD 34 HM 7.0 54.3 24440.2 1 n.f. n.f. OS 34 1/60 10.6 77.6 1245.6 1 26 f 27 OD 2 0.2 0.0 91.8 127.4 1 17 G863A 28 Q1412X OS 2 0.6 0.0 94.9 69.2 1 27 m 25 OD 1 0.3 0.0 70.7 5670.4 1 n.f. n.f. OS 1 0.4 0.0 75.6 764.9 1 28 m 17 OD 3 0.2 0.8 67.3 4244.1 1 - - - - OS 3 0.3 0.0 80.6 2429.2 1 29 m 28 OD 2,5 0.1 5.4 80.8 795.0 1 - - - - OS 2,5 0.1 4.2 64.3 2101.1 1 30 f 27 OD 20 0.1 6.7 88.2 183.6 1 G1961E G1961E OS 20 0.1 10.9 81.0 448.2 1 Dis. dur., disease duration (years); HM, recognition of hand movements; VA, visual acuity in European decimals. Login to comment
183 of PRL ABCA4 allel1 exon mut 1 ABCA4 allel2 exon mut 2 1 m 32 OD 2 0.4 0.0 90.0 211.0 1 48 L2241V n.f. OS 2 0.6 0.0 90.0 181.6 1 2 f 55 OD 29 0.1 9.7 60.3 9874.6 1 - - - - OS 29 0.1 6.8 67.5 68260.1 2 3 f 38 OD 16 0.05 6.4 73.7 4962.8 1 14 W663X 42 G1961E OS 7 0.4 0.0 90.9 143.5 1 4 m 23 OD 7 0.1 5.7 81.8 664.3 1 40 R1898H 43 G1975R OS 6 0.1 7.0 80.6 594.2 1 5 m 16 OD 7 0.05 7.4 81.0 1052.0 1 12+21 L541P+ 40 IVS40+5 OS 7 0.05 5.0 73.3 11500.0 1 A1038V G->A 6 m 34 OD 34 0.1 0.0 76.2 924.2 1 n.f. n.f. OS 34 0.1 0.0 74.3 1106.2 1 7 m 17 OD 11 0.1 3.1 79.1 3517.6 1 - - - - OS 11 0.1 3.6 70.0 2226.1 1 8 m 46 OD 14 0.5 3.6 80.6 3986.2 1 11 E471K 42 G1961E OS 14 0.2 3.7 58.3 40731.5 1 9 f 26 OD 15 0.1 6.0 70.5 3215.2 1 17 G863A n.f. OS 15 0.1 8.5 56.5 14734.9 1 10 f 19 OD 2 0.1 7.9 65.7 3260.0 1 3 P68L 36 S1689P OS 2 0.1 7.0 63.9 2964.8 1 11 f 34 OD 30 0.4 0.0 88.2 234.1 1 28 E1399K 42 G1961E OS 30 0.4 0.0 87.9 350.0 1 12 m 59 OD 5 0.1 5.2 79.2 1715.5 1 42 G1961E n.f. OS 5 0.1 4.4 75.0 3839.5 1 13 m 35 OD 20 0.05 9.7 72.9 8164.8 1 17 G863A 37 Q1750X OS 20 0.05 10.3 64.9 9820.4 1 14 m 43 OD 29 HM 16.0 58.5 18228.0 1 17 G863A 37 Q1750X OS 29 HM 15.6 42.1 14173.5 1 15 f 32 OD 10 0.05 6.5 61.3 10195.5 1 21 A1038V n.f. OS 10 0.05 5.0 56.7 7560.7 1 16 m 46 OD 4 0.05 8.5 51.1 8641.6 1 12+21 L541P+ 17 G863A OS 4 0.3 5.0 51.1 19827.1 1 A1038V 17 m 43 OD 3 0.5 0.0 90.7 190.9 1 - - - - OS 3 0.7 0.0 81.9 402.2 1 18 f 31 OD 27 1/15 9.8 69.3 2268.5 1 22 R1108C n.f. OS 27 0.1 17.2 60.9 4237.0 1 19 f 23 OD 5 0.05 6.0 72.9 3751.2 1 28 E1399K 43 G1977S OS 5 0.05 6.2 74.8 3578.9 1 20 f 16 OD 5 0.1 6.0 75.8 708.0 1 22 R1108C n.f. OS 5 0.1 5.4 82.4 449.6 1 21 m 38 OD 23 0.1 8.2 53.7 53733.8 2 - - - - OS 12 0.1 6.2 60.3 80873.8 2 22 m 40 OD 6 0.05 16.6 60.8 11677.8 1 14 R681X n.f. OS 6 0.1 10.0 60.6 5134.5 1 23 f 24 OD 3 0.1 6.7 90.5 577.8 1 6 G768T/ n.f. OS 3 0.1 7.1 83.6 3015.2 1 splice 24 m 13 OD 3 0.05 6.9 65.2 1882.7 1 - - - - OS 3 0.05 7.3 53.7 3844.3 1 25 f 39 OD 34 HM 7.0 54.3 24440.2 1 n.f. n.f. OS 34 1/60 10.6 77.6 1245.6 1 26 f 27 OD 2 0.2 0.0 91.8 127.4 1 17 G863A 28 Q1412X OS 2 0.6 0.0 94.9 69.2 1 27 m 25 OD 1 0.3 0.0 70.7 5670.4 1 n.f. n.f. OS 1 0.4 0.0 75.6 764.9 1 28 m 17 OD 3 0.2 0.8 67.3 4244.1 1 - - - - OS 3 0.3 0.0 80.6 2429.2 1 29 m 28 OD 2,5 0.1 5.4 80.8 795.0 1 - - - - OS 2,5 0.1 4.2 64.3 2101.1 1 30 f 27 OD 20 0.1 6.7 88.2 183.6 1 G1961E G1961E OS 20 0.1 10.9 81.0 448.2 1 Dis. dur., disease duration (years); HM, recognition of hand movements; VA, visual acuity in European decimals. Login to comment

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

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

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

[hide] 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.

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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.

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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.

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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