Fig. 2: STGD1 ROs display a patient-specific photoreceptor mislocalisation that positively correlates with disease severity.

A At Day 120, basally located REC⁺ photoreceptors are apparent in both patient and control ROs, as expected during this stage of retinogenesis. This phenotype persists at Day 180 in a patient-specific manner with the majority of photoreceptors having migrated to the apex (above white dashed line) as expected in WT2. OPN1MW/LW⁺ red/green cones being the most affected (white arrowheads). AC and PT1 ROs also display RHO⁺ rod mislocalisation. There is evidence of correctly aligned photoreceptors on the RO’s apical edge alongside positively stained OS in patient ROs also (shown above the dashed line) suggesting not all photoreceptors are affected. B Mislocalised OPN1MW/LW⁺ and RHO⁺ photoreceptors were quantified at Day 220 by counting the number of externally and internally positioned photoreceptor nuclei. External/Internal boundaries are defined by the white line across the central region of the RO. A significant decrease in external OPN1MW/LW⁺ cones in PT2, PT1 and AC was observed when compared with their respective WT2 controls. In contrast, internal OPN1MW/LW⁺ cones displayed a significant increase in PT2, PT1 and AC ROs. Significance was highest for the AC ROs which displayed the most enhanced phenotype. External RHO⁺ cells displayed a higher number of RHO⁺ cells in PT2 when compared with WT2, whilst AC ROs showed a significant decrease in externally aligned RHO⁺ cells. Statistics: One-way ANOVA. N = 5 ROs per triplicate - comparing only within protocol groups (e.g., BMP4-activated PT2 vs WT2). * = p-val 0.05, ** = p-val 0.01, *** = p-val 0.001, **** = p-val 0.0001.