DRAM2 – Cone-rod Dystrophy

Biallelic variants in DRAM2 have been implicated in autosomal recessive cone-rod dystrophy, characterized by adult-onset macular degeneration progressing to peripheral retinal involvement. In a cohort of 279 inherited retinal dystrophy cases, whole exome sequencing identified three novel homozygous DRAM2 mutations—c.518-1G>A, c.693+2T>A, and c.628_629insAG (p.Ala210GlufsTer16)—in three unrelated probands, with cosegregation confirmed in three families ([PMID:31394102]). Affected individuals presented with central vision loss in the third to fourth decade, fundus autofluorescence showing macular atrophy, and full-field electroretinography consistent with cone-rod dysfunction.

All three variants are predicted to disrupt DRAM2 transcript integrity: the splice-site mutations (c.518-1G>A, c.693+2T>A) and the frameshift insertion (c.628_629insAG (p.Ala210GlufsTer16)) lead to alternative splicing and premature termination, respectively. Segregation analysis across three pedigrees supports an autosomal recessive inheritance model with complete penetrance in homozygous individuals.

Functional assessment of patient-derived mRNA revealed aberrant splicing products, reduced transcript levels via activation of nonsense-mediated decay, and the presence of retina-specific DRAM2 isoforms; these findings correlate with phenotypic variability, where frameshift alleles exhibited milder mid-peripheral involvement and the in-frame splicing variant associated with more severe, widespread degeneration ([PMID:31394102]). Semi-quantitative RT-PCR across human tissues demonstrated ubiquitous DRAM2 expression with a distinct retina-brain pattern, underscoring its critical role in photoreceptor autophagy and survival.

Mechanistically, loss of DRAM2 function likely impairs autophagic flux in photoreceptors and retinal pigment epithelium, leading to progressive cone and rod cell loss. The concordance of genetic, segregation, and transcriptional data satisfies ClinGen criteria for a Strong gene-disease association and Moderate genetic and functional evidence tiers. Further studies in cellular and animal models could refine the pathogenic mechanism.

Key Take-home: Homozygous DRAM2 loss-of-function mutations cause autosomal recessive cone-rod dystrophy via disrupted autophagy and NMD-mediated transcript loss, informing molecular diagnosis and potential therapeutic targeting.

References

• Experimental Eye Research • 2019 • Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations. PMID:31394102

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