ABCMdb

PMID: 25301883

Noupuu K, Lee W, Zernant J, Tsang SH, Allikmets R
Structural and genetic assessment of the ABCA4-associated optical gap phenotype.
Invest Ophthalmol Vis Sci. 2014 Oct 9;55(11):7217-26. doi: 10.1167/iovs.14-14674., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCA4 p.Gly1961Glu At least two disease-causing ABCA4 variants where identified in each patient; all except one (91%) were compound heterozygous for the p.G1961E mutation. Login to comment 18 ABCA4 p.Gly1961Glu This particular phenotype also appears to be highly associated with the p.G1961E mutation of ABCA4. Login to comment 20 ABCA4 p.Gly1961Glu Keywords: ABCA4, Stargardt disease, optical gap, p.G1961E mutation, optical coherence tomography Stargardt disease (STGD1) is an early-onset autosomal recessive macular dystrophy with a reported prevalence between 1:8000 to 1:10,000, making it the most common form of juvenile macular disease.1 Stargardt disease is caused by mutations in the ABCA4 gene, which encodes an adenosine triphosphatase (ATP)-binding cassette transporter located in the outer segments of photoreceptors.2 ABCA4 performs an important function in the visual cycle being responsible for flipping of all-trans- and 11-cis-retinoids from the intradiscal space to the cytoplasm.3 Mutations in ABCA4 result in the accumulation of protonated N-retinylidene-PE (N-ral-PE) in the photoreceptor outer segments along with a secondary accumulation of N-retinylidene-N-retinyl-ethanolamine (A2E) in the RPE cells during the process of disc shedding and subsequent phagocytosis.4,5 The excess of A2E has been associated with a toxic effect on RPE cells resulting in cell death.6,7 In addition to phenotypic heterogeneity within the clinical spectrum of STGD1,8 mutations in ABCA4 have been reported in other retinal degenerative diseases such as cone-rod dystrophy,9 autosomal recessive retinitis pigmentosa,10,11 and AMD.12 Stargardt disease often initially presents with early atrophic changes in the macula and white-yellow pisciform flecks, but can vary in time from the appearance of bull`s eye maculopathy13 to extensive chorioretinal atrophy.14,15 Several grading systems have been established to characterize the overall progression of STGD1 phenotype.14,16 Functionally, STGD1 can be staged into three groups with respect to electrophysiological findings of the outer retina: Group 1 exhibits pattern electroretinography (pERG) abnormalities, but normal full-field photopic and scotopic responses, group 2 exhibits changes in isolated photopic function and group 3 exhibits significant dysfunction in both the scotopic and photopic systems.16 A less common previously documented phenotype within the STGD1 clinical spectrum is the optical gap, also referred to as an optical empty lesion or foveal cavitation.13,17,18 In addition to STGD1, optical gaps have been described in solar retinopathy, rod monochromatism, and maculopathies associated with RP1L1 mutations.19-23 The optical gap is exclusively detectable by spectral-domain optical coherence tomography (SD-OCT) and appears to represent a focal loss of ellipsoid zone (EZ) reflectance in the outer fovea.17 The aim of this study was to characterize the optical gap phenotype according to its developmental stages and to investigate its association with specific ABCA4 mutations. Login to comment 67 ABCA4 p.Gly1961Glu Interestingly, 91% of unrelated cases were compound heterozygous for the p.G1961E variant. Login to comment 68 ABCA4 p.Gly1961Glu Therefore, the allele frequency of p.G1961E in patients with the optical gap phenotype in this study was 46.7% and in our entire STGD1 cohort it is 13.4% (see below and Supplementary Tables S1, S2), which results in a highly statistically significant difference (v2 &#bc; 20.9; P &#bc; 5 3 106). Login to comment 79 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Asp [286A > G];[5882G > A] p.[(N96D)];[(G1961E)] P2, F*ߤ c. Login to comment 80 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Asp [286A > G];[5882G > A] p.[(N96D)];[(G1961E)] P3, M* c. Login to comment 83 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [1622T > C;3113C > T];[5882G > A] p.[(L541P;A1038V)];[(G1961E)] P6, F*ߤ c. Login to comment 84 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [1622T > C;3113C > T];[5882G > A] p.[(L541P;A1038V)];[(G1961E)] P7, F*ߤ c. Login to comment 85 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [1622T > C];[5882G > A] p.[(L541P)];[(G1961E)] P8, F*ߤ c. Login to comment 86 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [1622T > C];[5882G > A] p.[(L541P)];[(G1961E)] P9, Fߤ c. Login to comment 87 ABCA4 p.Gly1961Glu ABCA4 p.Cys2150Arg [5882G > A];[6448T > C] p.[(G1961E)];[(C2150R)] P10, Fߤ c. Login to comment 88 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu [4139C > T];[5882G > A] p.[(P1380L)];[(G1961E)] P11, M c. Login to comment 91 ABCA4 p.Gly1961Glu ];[(G1961E)] P13, Mߤ c. Login to comment 92 ABCA4 p.Trp821Arg ABCA4 p.Cys2150Tyr [2461T > A];[6449G > A] p.[(W821R)];[(C2150Y)] P14, F c. Login to comment 94 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro [1622T > C;4328G > A];[5882G > A] p.[(L541P;R1443H)];[(G1961E)] * Sibling pairs: P1 and P2, P3 and P4, P5 and P6, P7 and P8. Login to comment 182 ABCA4 p.Gly1961Glu Interestingly, the p.G1961E variant was present in 10 of 11 unrelated cases (91%). Login to comment 183 ABCA4 p.Gly1961Glu The p.G1961E mutation is the most frequent disease-associated ABCA4 allele seen in approximately 10% of STGD1 patients of European origin.34 This fraction was almost the same in our cohort of 179 patients, including 157 unrelated individuals (42/157; 13.4%), but strikingly higher in patients with the optical gap phenotype (46.7% vs. 13.4%, P < 0.0001). Login to comment 184 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu It has to be noted, however, that while the optical gap phenotype is definitely associated with the p.G1961E variant, the reverse is not the case since a larger fraction (32 unrelated individuals) who harbored the p.G1961E allele did not present with optical gap. Login to comment 186 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Of the other disease-associated ABCA4 alleles compound heterozygous with p.G1961E, the p.L541P mutation, presenting alone or as a complex allele with the p.A1038V variant, was observed in seven cases (four unrelated) with optical gap (Table 2 and Supplementary Table S1) while only once in patients without the phenotype (Supplementary Table S1). Login to comment 188 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu With the exception of P13, the optical gap was not observed in the SD-OCT scans of any other non-p.G1961E patients (n &#bc; 131) whose age at time of examination, age of onset and estimated disease duration were not statistically different from those of p.G1961E (n &#bc; 48) patients (Supplementary Table S2). Login to comment 189 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro Therefore, we can conclude that the p.G1961E variant, maybe sometimes together with the p.L541P or p. (L541P; A1038V) allele, is currently the only ABCA4 mutation associated with the optical gap phenotype. Login to comment 191 ABCA4 p.Gly1961Glu A striking association of the optical gap phenotype with the p.G1961E mutant allele in the ABCA4 gene was observed; however, further studies on larger patient cohorts are needed to validate this phenotype-genotype correlation and determine the functional association. Login to comment 241 ABCA4 p.Gly1961Glu Cella W, Greenstein VC, Zernant-Rajang J, et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull`s eye maculopathy. Login to comment 317 ABCA4 p.Gly1961Glu Burke TR, Fishman GA, Zernant J, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Login to comment