DRAM2 中的双等位基因突变会导致常染色体隐性遗传锥杆营养不良症，称为 CORD21，通常出现在生命的三至六十岁之间。尽管 DRAM2 定位于感光细胞和视网膜色素上皮 (RPE) 细胞的溶酶体，但其在视网膜变性中的具体作用尚未完全阐明。在这项研究中，我们从两名 CORD21 患者的诱导多能干细胞 (iPSC) 中生成并表征了视网膜类器官 (RO) 和 RPE 细胞。我们的研究表明，CORD21-RO 和 RPE 细胞表现出脂质代谢异常、自噬流缺陷、异常溶酶体含量积累以及溶酶体酶活性降低。我们发现了 DRAM2 与囊泡运输蛋白的潜在相互作用，表明它参与了这一细胞过程。这些发现共同表明，DRAM2 通过调节溶酶体功能、自噬和潜在的囊泡运输，在维持光感受器和 RPE 细胞的完整性方面发挥着至关重要的作用。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.