Clinical features and molecular mechanisms of RP1L1 variants causing occult macular dystrophy

Occult macular dystrophy (OMD) is an inherited retinopathy characterized by progressive bilateral vision loss despite normal findings on fundoscopic examination, fluorescein angiography, and full-field electroretinography. Its pathogenesis remains unknown, and no treatments are available. Here, we performed whole-exome sequencing on 133 samples from 78 OMD pedigrees to identify pathogenic variants, using filters for minor allele frequency, function prediction, and retinal expression. We identified the RP1L1 c.133C>T, p.Arg45Trp (R45W) mutation as the sole pathogenic variant in two families with dominantly inherited OMD. Additionally, we discovered five other potentially pathogenic RP1L1 variants. Together, these six variants accounted for 33.33% of pedigrees, with R45W being the most prevalent, at 16.6%. The R45W mutation correlated with earlier onset, more severe clinical phenotypes, and abnormal intracellular localization rather than altered expression levels. R45W disrupted the intracellular localization of RP1L1 and RP1, compromising cell viability. In induced photoreceptor-like cells derived from OMD patients carrying R45W, we observed downregulation of the long noncoding RNA MEG3 and the PI3K/Akt pathway, alongside upregulation of extracellular matrix organization. These findings validate the etiologic role of RP1L1 and offer insights into the pathogenesis of OMD, thereby facilitating future research and therapeutic development.