Dysregulation of Retinal and Photoreceptor Structural Integrity Genes in ATF6^-/- Retinal Organoids

ATF6 is a key regulator of the unfolded protein response (UPR) pathway that maintains cellular homeostasis during ER stress. In people, loss of ATF6 function causes cone dysfunction, manifesting as achromatopsia (ACHM). Previously, we generated ACHM retinal organoids (ROs) from patient induced pluripotent stem cells (iPSCs) carrying mutant ATF6 variants and gene-edited ATF6-knockout (KO) human embryonic stem cells (hESCs). ACHM and ATF6-KO ROs both showed severe stunting of cone inner and outer segments. RNA-Seq analysis of ACHM 290-day-old ROs showed downregulated cone gene expression and dysregulated mitochondria and ER stress gene expression. Here, we analyzed RNA-Seq analysis of 203-day-old ATF6-KO ROs. In younger ROs, we found dysregulation of genes involved in retinal and photoreceptor structural integrity, including CRB1, EGFLAM, and VTN. In addition, we found dysregulation of ATF6 and UPR-regulated transcriptional signatures. Dysregulation of retinal and photoreceptor structural integrity genes may underlie the observed stunting of cone inner/outer segments in ATF6-achromatopsia patients.