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  • Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients. The American journal of pathology Lee, E., Diaz-Aguilar, M. S., Min, H., Choi, J., Valdez Duran, D. A., Grandjean, J. M., Wiseman, R. L., Kroeger, H., Lin, J. H. 2022


    Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk-RNA-seq transcriptomes from retinal-organoids generated from ACHM patients carrying homozygous loss-of-function ATF6 variants. We identified marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids, indicating that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, we compared gene expression from control and ACHM retinal organoids with transcriptome profiles of 7 major retinal cell types generated from recent single-cell transcriptomic maps of non-diseased human retina. Our analysis revealed pronounced down-regulation of cone genes and up-regulation in Muller glia genes, with no significant effects on other retinal cells. Overall, our analysis of ACHM patient retinal organoids identifies new cellular and molecular phenotypes in addition to cone dysfunction: activation of Muller cells, increased ER stress, and disrupted mitochondrial structure and elevated respiratory chain activity gene expression.

    View details for DOI 10.1016/j.ajpath.2022.12.002

    View details for PubMedID 36535406