DRAM2 – cone-rod dystrophy 21

DRAM2 encodes a lysosomal membrane protein expressed in photoreceptors and retinal pigment epithelium. Biallelic loss-of-function variants in DRAM2 cause autosomal recessive cone-rod dystrophy 21 (CORD21), typically presenting in the third to sixth decades with macular involvement followed by peripheral degeneration. Initial genetic studies in three unrelated families identified homozygous splice and insertion mutations segregating with disease ([PMID:31394102]). A representative allele, c.628_629insAG (p.Ala210GlufsTer16) ([PMID:31394102]), exemplifies the frameshift variants leading to reduced mRNA via nonsense-mediated decay.

Subsequent stem cell–derived retinal organoid analyses from two CORD21 patients confirmed lipid metabolism abnormalities, impaired autophagic flux, lysosomal enzyme deficiency, and accumulation of aberrant lysosomal content ([PMID:38964324]). These functional defects correlate with photoreceptor loss in patient organoids and RPE cells, implicating disrupted autophagy and vesicular trafficking in pathogenesis. Complementary hPSC and mouse models demonstrate that DRAM2 deficiency exacerbates photoreceptor degeneration and choroidal neovascular changes, highlighting cell type-specific effects on survival and proliferation ([PMID:37691820]).

Overall, five unrelated probands (3 families [PMID:31394102], 2 patients [PMID:38964324]) with cosegregating biallelic DRAM2 variants provide strong genetic evidence. Functional concordance across patient cells and animal systems supports a disease mechanism of autophagy insufficiency. No conflicting reports have been described to date. Genetic testing for DRAM2 variants enables definitive diagnosis of CORD21, informs prognosis, and guides research into autophagy-targeted therapies.

References

• Experimental eye research • 2019 • Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations. [PMID:31394102]
• Frontiers in cell and developmental biology • 2023 • Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy. [PMID:37691820]
• Stem cell reports • 2024 • Retinal cells derived from patients with DRAM2-dependent CORD21 dystrophy exhibit key lysosomal enzyme deficiency and lysosomal content accumulation. [PMID:38964324]

Evidence Based Scoring (AI generated)