ABCMdb

PMID: 19217903

Cella W, Greenstein VC, Zernant-Rajang J, Smith TR, Barile G, Allikmets R, Tsang SH
G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy.
Exp Eye Res. 2009 Jun 15;89(1):16-24. Epub 2009 Feb 13., [PubMed]

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0 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull`s eye maculopathy Wener Cella a , Vivienne C. Greenstein a,c , Jana Zernant-Rajang a , Theodore R. Smith a , Gaetano Barile a , Rando Allikmets a,b,**, Stephen H. Tsang a,b,* a Department of Ophthalmology, Bernard and Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, Columbia University, 160 Fort Washington Avenue, New York, NY 10032, USA b Department of Pathology and Cell Biology, Bernard and Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, Columbia University, 160 Fort Washington Avenue, New York, NY 10032, USA c Department of Ophthalmology, School of Medicine, New York University, NYU Langone Medical Center, 550 First Avenue, New York, NY 10016, USA a r t i c l e i n f o Article history: Received 15 October 2008 Accepted in revised form 4 February 2009 Available online 13 February 2009 Keywords: stargardt mutation maculopathy retinal degeneration dystrophy a b s t r a c t The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Login to comment 1 ABCA4 p.Gly1961Glu Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Login to comment 8 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu DNA analysis revealed that 3 patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. Login to comment 9 ABCA4 p.Gly1961Glu The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Login to comment 10 ABCA4 p.Gly1961Glu Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull`s eye maculopathy in either the homozygosity or heterozygosity state. Login to comment 31 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Our aim in this study is to characterize the pathological and functional consequences of the G1961E allele in the ABCA4 gene, and we report an association between group 1 STGD1 patients with bull`s eye maculopathy and homozygous or heterozygous G1961E mutations. Login to comment 32 ABCA4 p.Gly1961Glu We also describe in detail (for the first time in the literature to our knowledge) the phenotype of homozygous G1961E mutation as observed in 3 patients. Login to comment 33 ABCA4 p.Gly1961Glu We found that the G1961E mutation is associated with early foveal disorganization of photoreceptor outer segment that appear before clinically evident RPE damage. Login to comment 36 ABCA4 p.Gly1961Glu Subjects Clinical records of 15 patients (from 11 unrelated families) with the G1961E allele and bull`s eye maculopathy based on fundus autofluorescence (FAF) were examined. Login to comment 74 ABCA4 p.Gly1961Glu Screening for G1961E mutations The screening for mutations in the ABCA4 gene was performed using the ABCR400 micro-array (Jaakson et al., 2003) that detects all currently described disease-associated variants in the ABCA4 gene (496), and confirmed by direct sequencing. Login to comment 82 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Patients were classified as either G1961E/G1961E homozygous, or compound heterozygous (G1961E and another mutant allele). Login to comment 88 ABCA4 p.Gly1961Glu Three patients were homozygous for the G1961E allele and 12 were compound heterozygotes. Login to comment 89 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Gln636His ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Thr1253Met ABCA4 p.Thr1253Met ABCA4 p.Arg2077Trp ABCA4 p.Arg2077Trp ABCA4 p.Asp1532Asn ABCA4 p.Asp1532Asn Of the compound heterozygous group, 5 patients from 2 families had the complex mutation L541P/A1038V, 2 patients (siblings) had the splicing mutation IVS20 þ 5G / A, and 5 patients had missense mutations Q636H, R2077W, T1253M, C54Y and D1532N (Table 1). Login to comment 106 ABCA4 p.Gly1961Glu Genetic analysis For further analysis, we grouped patients according to G1961E segregation. Login to comment 109 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Homozygous G1961E/G1961E mutation Phenotypic consequences for homozygous G1961E/G1961E have yet to be reported, despite the fact that has been considered one of the most frequent variants in AMD and the Stargardt (Lewis et al., 1999). Login to comment 110 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu G1961E/G1961E causes bull`s eye maculopathy in these unrelated patients with varying disease onset age and duration. Type B bull`s eye maculopathy was found in 2 patients and type A in one (Fig. 4). Login to comment 121 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Compound heterozygous G1961E mutation Twelve patients were ABCA4 compound heterozygous with the G1961E allele. Login to comment 122 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Five patients from 2 unrelated families carried the complex mutation L541P/A1038V in addition to the G1961E allele. Login to comment 128 ABCA4 p.Gly1961Glu Two patients from family 6 had the G1961E allele paired with cryptic splice site mutation IVS20 þ 5G / A, resulting in early-onset, rapid progression, and moderately-to-severely impaired visual acuity. Login to comment 131 ABCA4 p.Gly1961Glu ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Thr1253Met ABCA4 p.Arg2077Trp ABCA4 p.Asp1532Asn In 5 patients (patients 7-11), missense mutations Q636H, R2077W, T1253M, C54Y and D1532N were found in addition to the G1961E allele, respectively. Login to comment 134 ABCA4 p.Gly1961Glu Discussion G1961E is one of the most frequently observed mutant ABCA4 alleles (Allikmets et al., 1997; Gerth et al., 2002; Simonelli et al., 2005). Login to comment 135 ABCA4 p.Gly1961Glu Discussion G1961E is one of the most frequently observed mutant ABCA4 alleles (Allikmets et al., 1997; Gerth et al., 2002; Simonelli et al., 2005). Login to comment 137 ABCA4 p.Gly1961Glu Our study demonstrates that the G1961E allele in either the homozygous or heterozygous state is associated with bull`s eye maculopathy and early central photoreceptor disorganization, resulting in reduced pattern electroretinogram (PERG) P50 responses. Login to comment 138 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu As our G1961E patients have normal full-field ERGs and abnormal PERG, we hypothesize that this mutant allele is associated with retinal dysfunction restricted to the macula, and it is not associated with generalized retinal dysfunction. Login to comment 139 ABCA4 p.Gly1961Glu As our G1961E patients have normal full-field ERGs and abnormal PERG, we hypothesize that this mutant allele is associated with retinal dysfunction restricted to the macula, and it is not associated with generalized retinal dysfunction. Login to comment 141 ABCA4 p.Gly1961Glu In normal subjects, Table 1 Summary of clinical and genetic data of patients with both homozygous and heterozygous G1961E mutation. Login to comment 142 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Thr1253Met ABCA4 p.Arg2077Trp ABCA4 p.Asp1532Asn Case #, sex Age of onset Duration (years) Visual acuity (OD, OS) Allele 2 Bull`s eye type (FAF) SD-OCT MP-1 1, f 20 1 20/25, 20/40 G1961E (homozygous) B Not tested Not tested 2, f 49 13 20/200, 20/150 G1961E (homozygous) B Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 4 degrees OD and in the central 6 degrees OS, eccentric PRL (superior retina) 3, m 19 13 20/70, 20/70 G1961E (homozygous) A Not tested Absolute scotoma in the central 6 degrees in both eyes, eccentric PRL (superior retina) 4.1, f 17 30 20/200, 20/200 L541P/A1038V B Not tested Not tested 4.2, m 28 2 20/25, 20/30 L541P/A1038V B Not tested Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 4.3, m 28 2 20/30, 20/40 L541P/A1038V B Not tested Decreased sensitivity by 9 dB OD and 11 dB OS in the central 2 degrees, foveal fixation 5.1, f 14 5 20/200, 20/400 L541P/A1038V C Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Decreased sensitivity by 8 dB in the central 2 degrees in both eyes, eccentric PRL (superior retina) 5.2, f 14 1 20/20, 20/25 L541P/A1038V A Photoreceptor disorganization, normal ONL and normal RPE Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 6.1, f 17 5 20/100, 20/100 IVS20 þ 5G / A C Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 2 degrees in both eyes, eccentric PRL (superior retina) 6.2, m 14 3 20/40, 20/25 IVS20 þ 5G / A A Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Absolute scotoma in the central 2 degrees OD and decreased sensitivity by 18 dB in the central 2 degrees OS, eccentric PRL (superior retina) 7, m 28 12 20/200, 20/150 Q636H B Photoreceptor loss, thinner ONL and RPE atrophy Not tested 8, f 25 9 20/80, 20/25 R2077W B Not tested Not tested 9, m 67 2 20/800, 20/60 T1253M B Not tested Not tested 10, f 26 10 20/80, 20/80 C54Y B Not tested Not tested 11, f 44 20 20/400, 20/60 D1532N C Not tested Absolute scotoma in the central 8-10 degrees OD and absolute scotoma in the central 8 degrees OS, eccentric PRL (superior retina) Abbreviations: m, male; f, female; OD, right eye; OS, left eye; FAF, fundus autofluorescence; bull`s eye type A, presence of a ring of increase autofluorescence surrounding decreased autofluorescence; bull`s eye type B, decreased fovea autofluorescence without a surrounding ring of increase autofluorescence; bull`s eye type C, speckled macular appearance with slightly increased surround autofluorescence; SD-OCT, spectral-domain optical coherence tomography; ONL, outer nuclear layer; MP-1, microperimetry; and PRL, preferred retinal location. Login to comment 143 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Thr1253Met ABCA4 p.Arg2077Trp ABCA4 p.Asp1532Asn Case #, sex Age of onset Duration (years) Visual acuity (OD, OS) Allele 2 Bull`s eye type (FAF) SD-OCT MP-1 1, f 20 1 20/25, 20/40 G1961E (homozygous) B Not tested Not tested 2, f 49 13 20/200, 20/150 G1961E (homozygous) B Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 4 degrees OD and in the central 6 degrees OS, eccentric PRL (superior retina) 3, m 19 13 20/70, 20/70 G1961E (homozygous) A Not tested Absolute scotoma in the central 6 degrees in both eyes, eccentric PRL (superior retina) 4.1, f 17 30 20/200, 20/200 L541P/A1038V B Not tested Not tested 4.2, m 28 2 20/25, 20/30 L541P/A1038V B Not tested Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 4.3, m 28 2 20/30, 20/40 L541P/A1038V B Not tested Decreased sensitivity by 9 dB OD and 11 dB OS in the central 2 degrees, foveal fixation 5.1, f 14 5 20/200, 20/400 L541P/A1038V C Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Decreased sensitivity by 8 dB in the central 2 degrees in both eyes, eccentric PRL (superior retina) 5.2, f 14 1 20/20, 20/25 L541P/A1038V A Photoreceptor disorganization, normal ONL and normal RPE Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 6.1, f 17 5 20/100, 20/100 IVS20 &#fe; 5G / A C Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 2 degrees in both eyes, eccentric PRL (superior retina) 6.2, m 14 3 20/40, 20/25 IVS20 &#fe; 5G / A A Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Absolute scotoma in the central 2 degrees OD and decreased sensitivity by 18 dB in the central 2 degrees OS, eccentric PRL (superior retina) 7, m 28 12 20/200, 20/150 Q636H B Photoreceptor loss, thinner ONL and RPE atrophy Not tested 8, f 25 9 20/80, 20/25 R2077W B Not tested Not tested 9, m 67 2 20/800, 20/60 T1253M B Not tested Not tested 10, f 26 10 20/80, 20/80 C54Y B Not tested Not tested 11, f 44 20 20/400, 20/60 D1532N C Not tested Absolute scotoma in the central 8-10 degrees OD and absolute scotoma in the central 8 degrees OS, eccentric PRL (superior retina) Abbreviations: m, male; f, female; OD, right eye; OS, left eye; FAF, fundus autofluorescence; bull`s eye type A, presence of a ring of increase autofluorescence surrounding decreased autofluorescence; bull`s eye type B, decreased fovea autofluorescence without a surrounding ring of increase autofluorescence; bull`s eye type C, speckled macular appearance with slightly increased surround autofluorescence; SD-OCT, spectral-domain optical coherence tomography; ONL, outer nuclear layer; MP-1, microperimetry; and PRL, preferred retinal location. Login to comment 149 ABCA4 p.Gly1961Glu Lipofuscin accumulation leads to photoreceptor damage (Sparrow and Boulton, 2005) and our findings suggest that damage to the photoreceptor outer segment architecture is among the earliest signs of pathology in patients carrying the G1961E mutation. Login to comment 150 ABCA4 p.Gly1961Glu Lipofuscin accumulation leads to photoreceptor damage (Sparrow and Boulton, 2005) and our findings suggest that damage to the photoreceptor outer segment architecture is among the earliest signs of pathology in patients carrying the G1961E mutation. Login to comment 154 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Upon subgroup analysis based on ABCA4 allelic combinations, we found that the 3 homozygous G1961E/G1961E patients had retinal changes limited to the central macula. Login to comment 155 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Manifestation of bull`s eye maculopathy in these patients suggests that G1961E is a disease-causing mutation rather than a neutral polymorphism (Guymer et al., 2001). Login to comment 156 ABCA4 p.Gly1961Glu Manifestation of bull`s eye maculopathy in these patients suggests that G1961E is a disease-causing mutation rather than a neutral polymorphism (Guymer et al., 2001). Login to comment 157 ABCA4 p.Gly1961Glu G1961E decreases ATP-binding and ATPase activity (Sun and Nathans, 1997) and is considered a pathologic mutation that cosegregates with STGD1 (Lewis et al., 1999). Login to comment 158 ABCA4 p.Gly1961Glu G1961E is associated with milder phenotypes in homozygous (Fishman et al., 1999) or compound heterozygous states (Simonelli et al., 2005). Login to comment 159 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu In other words, patients who are homozygous or compound heterozygous for the G1961E allele Fig. 1. Login to comment 160 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Bull`s eye maculopathy in patient 1 with homozygous G1961E/G1961E mutation. Login to comment 161 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Bull`s eye maculopathy in patient 1 with homozygous G1961E/G1961E mutation. Login to comment 164 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro In the compound heterozygous group, 5 patients had the complex mutation allele L541P/A1038V, in addition to G1961E. Login to comment 165 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro In the compound heterozygous group, 5 patients had the complex mutation allele L541P/A1038V, in addition to G1961E. Login to comment 168 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro The L541P/A1038V mutation has been described in patients with more favorable clinical prognosis (Hargitai et al., 2005). Login to comment 169 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Similarly, although G1961E is considered a ''mild- to-moderate`` allele, it has been reported in bull`s eye maculopathy with more severe phenotype such as extensive atrophic RPE changes (Gerth et al., 2002; Simonelli et al., 2005). Login to comment 170 ABCA4 p.Gly1961Glu Similarly, although G1961E is considered a ''mild- to-moderate`` allele, it has been reported in bull`s eye maculopathy with more severe phenotype such as extensive atrophic RPE changes (Gerth et al., 2002; Simonelli et al., 2005). Login to comment 172 ABCA4 p.Gly1961Glu Bull`s eye maculopathy phenotypes associated with G1961E mutations. Login to comment 173 ABCA4 p.Gly1961Glu Bull`s eye maculopathy phenotypes associated with G1961E mutations. Login to comment 175 ABCA4 p.Gly1961Glu SD-OCT of patients carrying the G1961E mutation. Login to comment 176 ABCA4 p.Gly1961Glu SD-OCT of patients carrying the G1961E mutation. Login to comment 180 ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Asp1532Asn Visual acuity level related to disease duration was also observed in patients 7, 10 and 11 with missense mutations Q636H, C54Y and D1532N. Login to comment 182 ABCA4 p.Gln636His ABCA4 p.Cys54Tyr ABCA4 p.Thr1253Met ABCA4 p.Asp1532Asn An exception was patient 9 with the missense mutation T1253M that imparts an amino acid change outside of ABCA4 functional domain and presented with poor visual acuity but uncertain disease duration. Login to comment 184 ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met ABCA4 p.Arg2077Trp Finally, patient 8 had the missense mutation R2077W in addition to the G1961E allele and a mild-to-moderate phenotype, with asymmetrical visual acuity and discrete autofluorescence changes. Login to comment 185 ABCA4 p.Arg2077Trp Although the R2077W mutation occurs within the second nucleotide-binding domain of ABCA4 (Lewis et al., 1999), it did not appear to cause severe disease phenotype. Login to comment 186 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Arg2077Trp Our study confirms that the G1961E allele in either homozygosity or compound heterozygosity causes bull`s eye maculopathy featuring photoreceptor outer segment disruption as the earliest detectable finding. Login to comment 187 ABCA4 p.Arg2077Trp Although the R2077W mutation occurs within the second nucleotide-binding domain of ABCA4 (Lewis et al., 1999), it did not appear to cause severe disease phenotype. Login to comment 188 ABCA4 p.Gly1961Glu Our study confirms that the G1961E allele in either homozygosity or compound heterozygosity causes bull`s eye maculopathy featuring photoreceptor outer segment disruption as the earliest detectable finding. Login to comment 192 ABCA4 p.Gly1961Glu In conclusion, the G1961E mutant allele in either homozygosity or heterozygosity is associated with localized macular changes rather than generalized retinal dysfunction (Fishman et al., 1999; Lewis et al., 1999; Lois et al., 2004). Login to comment 194 ABCA4 p.Gly1961Glu In conclusion, the G1961E mutant allele in either homozygosity or heterozygosity is associated with localized macular changes rather than generalized retinal dysfunction (Fishman et al., 1999; Lewis et al., 1999; Lois et al., 2004). Login to comment 196 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Bull`s eye maculopathy associated with homozygous G1961E/G1961E mutation. Login to comment 198 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Bull`s eye maculopathy associated with homozygous G1961E/G1961E mutation. Login to comment