Multi-Exon Deletion Alleles of ATF6 Linked to Achromatopsia

Abstract

Purpose : Achromatopsia (ACHM) is an autosomal recessive cone photoreceptor dysfunction
disease. Patients have congenital severely impaired visual acuity, photoaversion, foveal
hypoplasia, and color vision defects. To date, 11 different ATF6A disease alleles have been
identified in ACHM patients. Here, we identified and characterized two additional multi-exon
spanning ATF6A disease alleles identified in ACHM patients.

Methods : Genetic sequencing were performed in three patients from two families with the cone
dysfunction. All three patients were clinically investigated by spectral domain-optical coherence
tomography (SD-OCT) and electroretinography (ERG). Triple-labeling In situ RNA
hybridization was performed using RNA scope assay. For the experiment, RNA oligo probes
specific for the mRNA of human retinal cone arrestin-3 (Arr3), ATF6A, and ATF6B were used in
vertical cross-sections of the human retina.

Results : A homozygous deletion covering exons 8 to 14 of the ATF6A gene from two siblings
from one family was identified. In another patient, a heterozygous deletion covering exons 2 and
3 of the ATF6A gene was identified. All patients showed evidence of foveal hypoplasia and loss
of photopic ERG response. In addition, recombinant ATF6 proteins bearing these exon deletions
showed significantly impaired transcriptional activity compared to wild-type ATF6. Last, the
RNAscope assay revealed that ATF6A and the related ATF6B transcripts are both expressed in
cones and also throughout all retinal layers of normal human retina.

Conclusions : Overall, our data identifies additional loss-of-function ATF6A disease alleles
associated with human foveal disease and cone dysfunction. Our data also raises the possibility
that 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.