ABCMdb

PMID: 22312191

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., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val Familial discordance in Stargardt disease Tomas R. Burke,1,4 Stephen H. Tsang,1,2 Jana Zernant,1 R. Theodore Smith,1,3 Rando Allikmets1,2 1Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University, New York, NY; 2Department of Pathology and Cell Biology, Edward S. Harkness Eye Institute, Columbia University, New York, NY; 3Department of Biomedical Engineering, Columbia University, New York, NY; 4The Oxford Deanery, Prince Charles Eye Unit, King Edward VII Hospital, Windsor, United Kingdom 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. Login to comment 3 ABCA4 p.Trp663* Genotyping revealed the W663X stop mutation in all affected patients. Login to comment 4 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val 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. Login to comment 5 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val 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." Login to comment 19 ABCA4 p.Ala1038Val ABCA4 p.Trp663* 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 20 ABCA4 p.Ala1038Val ABCA4 p.Trp663* 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 ABCA4 p.Gly1961Glu ABCA4 p.Trp663* Patients 3 and 4 inherited the W663X mutation maternally and the G1961E mutation paternally. Login to comment 22 ABCA4 p.Gly1961Glu ABCA4 p.Trp663* Patients 3 and 4 inherited the W663X mutation maternally and the G1961E mutation paternally. Login to comment 27 ABCA4 p.Ala1038Val ABCA4 p.Trp663* DISCUSSION Both patients 1 and 2 were compound heterozygous for the W663X and A1038V mutations in the ABCA4 gene. Login to comment 28 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Trp663* ABCA4 p.Trp663* DISCUSSION Both patients 1 and 2 were compound heterozygous for the W663X and A1038V mutations in the ABCA4 gene. Login to comment 29 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Trp663* 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 30 ABCA4 p.Ala1038Val While the complex allele gives rise to an ABCA4 protein which mislocalizes within the photoreceptor with a consequent reduction in protein function, the protein associated with A1038V alone does not demonstrate mislocalization [12]. Login to comment 31 ABCA4 p.Gly1961Glu 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 32 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Trp663* 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 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Trp663* 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 34 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro A report by Cideciyan et al. describing age of disease onset in terms of "age of retina-wide disease initiation" (ADI) suggested that the G1961E mutation results in a much later ADI than the complex allele L541P/A1038V [18]. Login to comment 35 ABCA4 p.Gly1961Glu In this study the retinae of patients 3 and 4 (with the G1961E mutation), at ages of examination Figure 1. Login to comment 36 ABCA4 p.Gly1961Glu In this study the retinae of patients 3 and 4 (with the G1961E mutation), at ages of examination Figure 1. Login to comment 41 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Trp663* ABCA4 p.Trp663* ABCA4 p.Trp663* ABCA4 p.Trp663* 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 58 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val Qualitatively normal thickness RPE was also observed in regions with loss of IS/OS (F, white arrow).Corresponding size bars for A and B, C and D, and E and F are included in A, C and E, respectively Familial discordance in Stargardt disease Tomas R. Burke,1,4 Stephen H. Tsang,1,2 Jana Zernant,1 R. Theodore Smith,1,3 Rando Allikmets1,2 1Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University, New York, NY; 2Department of Pathology and Cell Biology, Edward S. Harkness Eye Institute, Columbia University, New York, NY; 3Department of Biomedical Engineering, Columbia University, New York, NY; 4The Oxford Deanery, Prince Charles Eye Unit, King Edward VII Hospital, Windsor, United Kingdom 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. Login to comment 61 ABCA4 p.Trp663* Genotyping revealed the W663X stop mutation in all affected patients. Login to comment 62 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val 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. Login to comment 63 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val 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." Login to comment