The +57C>T substitution in microRNA-184 is associated with microphthalmia, retinal detachment, and altered ocular development

Abstract Purpose: To expand the clinical and mechanistic understanding of the +57C>T seed-region mutation in miR-184 causing EDICT (endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal thinning) syndrome. Design: Cross-sectional analysis and laboratory confirmation Participants: 18 members of a four-generation family with known +57C>T miR-184 status Methods: We used optical biometry, corneal topography, and medical history to characterize the clinical phenotype. Carrier effects on ocular biometric measurements were estimated using polygenic linear mixed models incorporating a pedigree-derived kinship matrix, adjusted for age and sex. Patient-derived and control induced pluripotent stem cells (iPSCs) were generated and differentiated into corneal endothelial cells (CECs). Main Outcome Measures: Axial length, keratometry (in diopters), white-to-white corneal diameter, topography mapping, central and peripheral corneal thickness, and history of retinal detachment or corneal transplant were compared between mutation carriers and noncarriers, adjusting for age and sex. Cellular analysis was conducted with immunostaining (ZO-1, ATP1A1), morphometric quantification, qRT-PCR of endothelial markers, and transendothelial electrical resistance (TEER). Results: 10 of 18 family members were heterozygous for +57C>T, with retinal detachment occurring in 5/10 affected individuals compared to 0/8 unaffected individuals (p=0.04). Affected eyes had 2.2 mm shorter axial length (p=0.02), 9.3 D steeper mean keratometry (p=0.004), 1.6 mm smaller horizontal corneal diameter (p=0.0001), and 139-micrometer thinner central corneas (p=0.003). Mutant iPSC-derived CECs were associated with irregular borders, increased cell and nucleus area, widened intercellular gaps, disrupted ATP1A1 membrane localization, and reduced barrier function on TEER (all p<0.05). Gene expression analysis showed downregulation of COL4A1, COL4A3, and AQP1 with upregulation of COL8A1. Conclusions: The miR-184 +57C>T mutation produces a broad ocular phenotype that includes smaller, thinner corneas and microphthalmia. Mechanistically, it disrupts CEC junctional integrity, extracellular matrix and pump-related genes, supporting a role for miR-184 in coordinated anterior-posterior eye morphogenesis.