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Kyle Kim, Eun-Jin Lee, Wei-Chieh Chiang, Heike Kroeger, Chloe Xiaoke Bi, Daniel L Chao, Rebecca Mastey, Stephen Tsang, Leon Chea, Britta Baumann, Isabelle S Audo, Susanne Kohl, Anthony Moore, Luke Wiseman, Joseph Carroll, Jonathan H Lin; Multi-Exon Deletion Alleles of ATF6 Linked to Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2393.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia (ACHM) is an autosomal recessive cone photoreceptor dysfunctiondisease. Patients have congenital severely impaired visual acuity, photoaversion, fovealhypoplasia, and color vision defects. To date, 11 different ATF6A disease alleles have beenidentified in ACHM patients. Here, we identified and characterized two additional multi-exonspanning ATF6A disease alleles identified in ACHM patients.
Genetic sequencing were performed in three patients from two families with the conedysfunction. All three patients were clinically investigated by spectral domain-optical coherencetomography (SD-OCT) and electroretinography (ERG). Triple-labeling In situ RNAhybridization was performed using RNA scope assay. For the experiment, RNA oligo probesspecific for the mRNA of human retinal cone arrestin-3 (Arr3), ATF6A, and ATF6B were used invertical cross-sections of the human retina.
A homozygous deletion covering exons 8 to 14 of the ATF6A gene from two siblingsfrom one family was identified. In another patient, a heterozygous deletion covering exons 2 and3 of the ATF6A gene was identified. All patients showed evidence of foveal hypoplasia and lossof photopic ERG response. In addition, recombinant ATF6 proteins bearing these exon deletionsshowed significantly impaired transcriptional activity compared to wild-type ATF6. Last, theRNAscope assay revealed that ATF6A and the related ATF6B transcripts are both expressed incones and also throughout all retinal layers of normal human retina.
Overall, our data identifies additional loss-of-function ATF6A disease allelesassociated with human foveal disease and cone dysfunction. Our data also raises the possibilitythat ATF6-associated achromatopsia may arise from cone cell-autonomous and cone cell non-autonomous etiologies.
This is a 2020 ARVO Annual Meeting abstract.
Pedigrees and topography of disease-causing mutations identified in the patients. (A) Pedigree drawing of exons 8-14 ATF6 deletion and exons 2-3 ATF6 deletion patients. (B) The amino acid organization, protein topology, and functional domains of ATF6 are shown, and the positions of the ATF6 variants are mapped onto the schematic drawing.
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