RESUMEN
Biallelic mutations in DRAM2 lead to an autosomal recessive cone-rod dystrophy known as CORD21, which typically presents between the third and sixth decades of life. Although DRAM2 localizes to the lysosomes of photoreceptor and retinal pigment epithelium (RPE) cells, its specific role in retinal degeneration has not been fully elucidated. In this study, we generated and characterized retinal organoids (ROs) and RPE cells from induced pluripotent stem cells (iPSCs) derived from two CORD21 patients. Our investigation revealed that CORD21-ROs and RPE cells exhibit abnormalities in lipid metabolism, defects in autophagic flux, accumulation of aberrant lysosomal content, and reduced lysosomal enzyme activity. We identified potential interactions of DRAM2 with vesicular trafficking proteins, suggesting its involvement in this cellular process. These findings collectively suggest that DRAM2 plays a crucial role in maintaining the integrity of photoreceptors and RPE cells by regulating lysosomal function, autophagy, and potentially vesicular trafficking.
RESUMEN
Aims and method Structured clinical judgement tools provide scope for the standardisation of forensic service gatekeeping and also allow identification of heuristics in this decision process. The DUNDRUM-1 triage tool was completed retrospectively for 121 first-time referrals to forensic services in South Wales. Fifty were admitted to medium security, 49 to low security and 22 remained in open conditions. RESULTS: DUNDRUM-1 total scores differed appropriately between different levels of security. However, regression revealed heuristic anchoring on the 'legal process' and 'immediacy of risk due to mental disorder' items. Clinical implications Patient placement was broadly aligned with DUNDRUM-1 recommendations. However, not all triage items informed gatekeeping decisions. It remains to be seen whether decisions anchored in this way are effective. Declaration of interest Dr Mark Freestone gave permission for AUC values from Freestone et al. (2015) to be presented here for comparison.