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Retinal cells derived from patients with DRAM2-dependent CORD21 dystrophy exhibit key lysosomal enzyme deficiency and lysosomal content accumulation

ABSTRACT: Biallelic DRAM2 mutations cause an autosomal recessive cone-rod dystrophy named CORD21 typically manifesting by the third decade of life. DRAM2 localises to the lysosomes of photoreceptor and retinal pigment epithelium (RPE) cells, however, it remains unclear how DRAM2 contributes to retinal degeneration. Herein, we have derived and characterised retinal organoids (ROs) and RPE cells from two CORD21 induced pluripotent stem cells (iPSCs) lines. CORD21 ROs and RPE manifested abnormal lipid metabolism, autophagic flux defects, aberrant lysosomal content accumulations and reduced lysosomal enzyme activity. A combined proteomics and western blot approach revealed the involvement of DRAM2 in vesicular trafficking that was further corroborated by the immunofluorescent co-localisation of DRAM2 with clathrin adaptor-related proteins AP-1 and AP-3 in ROs. Collectively, our data suggest an indispensable role for DRAM2 in the maintenance of photoreceptors and RPE cells by overseeing the transport of lysosomal enzymes.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Majlinda Lako

PROVIDER: MSV000094178 | MassIVE | Tue Feb 27 05:53:00 GMT 2024

SECONDARY ACCESSION(S): PXD050186

REPOSITORIES: MassIVE

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