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Jana Sajovic, Andrej Meglič, Martina Jarc-Vidmar, Frans P.M. Cremers, Mubeen Khan, Zelia Corradi, Claire-Marie Dhaenens, Damjan Glavač, Aleš Maver, Marija Volk, Borut Peterlin, Marko Hawlina, Ana Fakin; Characterisation of Stargardt disease pathogenesis associated with the frequent ABCA4 mutation c.5714+5G>A. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2705.
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© ARVO (1962-2015); The Authors (2016-present)
To study the effect of ABCA4 mutation c.5714+5G>A on retinal structure and mRNA.
Sixteen patients were divided into two groups: group 1 harboured splicing mutation c.5714+5G>A in trans with a null mutation (6 patients); group 2 had two null mutations (10 patients). Visual acuity, autofluorescence and optical coherence tomography of the right eyes were analysed. Areas of definitely decreased autofluorescence (DDAF) and thickness of the outer nuclear layer (ONL) in the macula were measured. Correlation between the degree of retinal pigment epithelium (RPE) atrophy (DDAF area) and loss of photoreceptors (ONL thickness) was compared between groups using multiple linear regression. Mann-Whitney U Test was used for comparing sets of data. The effect of c.5714+5G>A on RNA splicing was analysed using reverse transcription (RT)-PCR of mRNA isolated from patient-derived photoreceptor progenitor cells (PPCs).
Age at the exam did not differ significantly between the two groups (33.5 vs 20.5 yrs; p>0.05). However, group 1 patients had significantly later median age of onset (17.5 vs 8.0 yrs; p<0.01) and significantly better visual acuity (0.2 vs 0.02; p<0.05). Median ONL thickness was significantly higher in group 1 (15.9 µm vs 0.5 µm; p<0.01), whereas median DDAF area was comparable between the groups (12.7 mm2 vs 15.1 mm2; p>0.05). Multiple linear regression showed a significant correlation between ONL thickness and DDAF area within each genotype group. For a similar RPE atrophy area, patients in group 1 have much better photoreceptor preservation (p<0.01). RT-PCR of mRNA from PPCs from a patient carrying c.4539+1G>T and c.5714+5G>A using primers in exons 38 and 44 showed a major normal product and minor exon 40 and exon 39/40 deletion products.
Patients harbouring ABCA4 mutation c.5714+5G>A displayed significantly milder phenotypes for all parameters, which is in accordance with our RNA results in PPCs and previous in vitro splice assays, suggesting that this is a moderately severe variant. Thicker ONL layer when compared to double null patients with DDAF of similar size suggests different disease pathogenesis characterised by predominant RPE loss and relative photoreceptor sparing in association with c.5714+5G>A allele.
This is a 2021 ARVO Annual Meeting abstract.
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