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

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Occult macular dystrophy (OMD) causes progressive vision loss with normal initial eye exams.
• The underlying cause and effective treatments for OMD remain unknown.

Purpose of the Study:

• To identify genetic variants responsible for inherited OMD.
• To elucidate the molecular mechanisms driving OMD pathogenesis.

Main Methods:

• Whole-exome sequencing was performed on 78 OMD pedigrees.
• Pathogenic variants were filtered by allele frequency, functional prediction, and retinal expression.
• Patient-derived cells were used to study cellular and molecular changes.

Main Results:

• The RP1L1 c.133C>T, p.Arg45Trp (R45W) mutation was identified as a key pathogenic variant in dominant OMD.
• Six RP1L1 variants accounted for 33.33% of OMD pedigrees, with R45W being the most common.
• R45W disrupted RP1L1/RP1 localization, affected cell viability, and altered MEG3/PI3K/Akt pathways and extracellular matrix organization in patient cells.

Conclusions:

• The RP1L1 gene plays a critical role in the etiology of OMD.
• Understanding these genetic and molecular disruptions provides a basis for future OMD research and therapeutic strategies.