Exploring extracellular vesicle MicroRNAs in Usher syndrome type 1B: Tear-Derived EVs as potential indicators of retinal health

TL;DR

This study explores tear-derived extracellular vesicles as non-invasive biomarkers for retinal health in Usher syndrome type 1B, identifying specific microRNAs linked to retinal function.

Contribution

The study identifies tear-derived EV miRNA signatures as potential non-invasive biomarkers for retinal degeneration in USH1B.

Findings

Tear-derived EVs showed higher miRNA load and diversity compared to RPE-derived EVs.

Specific miRNAs like hsa-miR-200a-3p and hsa-miR-194-5p were upregulated in patient tear EVs.

Downregulated miRNAs in patient RPE-derived EVs were linked to retinal structure and function pathways.

Abstract

Usher syndrome type 1B (USH1B) is a rare inherited disorder characterized by congenital deafness and progressive retinitis pigmentosa, caused by biallelic pathogenic variants in the MYO7A gene. We explored extracellular vesicles (EVs) from two sources: human tears and iPSC-derived RPE cells from USH1B patients and controls. Tear EVs were assessed as a non-invasive biomarker source, while RPE-derived EVs provided insights into disease mechanisms in a controlled, cell-type-specific context. Although RPE differentiation was successful and MYO7A expression levels were similar between patients and controls, Myosin VIIA was not detected by western blot in the patient-derived cells. We examined the EV cargo by small non-coding RNAs (sncRNAs) sequencing from iPSC-RPE apical site and tears to identify molecular signatures of retinal degeneration. Tear EVs showed higher load and diversity of miRNAs than RPE-derived EVs, reflecting a broader ocular origin. Comparative analysis revealed shared retinal sncRNAs (hsa-miR-204, hsa-miR-211, hsa-miR-181a-5p) and group-specific differences. Notably, when comparing to controls, hsa-miR-200a-3p and hsa-miR-194-5p were upregulated in patient tear EVs, while let-7i/c-5p and hsa-miR-320a/b, were downregulated in-patient RPE-derived EVs. Pathway analysis linked these sncRNAs to retinal structure and function, including cytoskeletal remodeling and junctional integrity. Our findings highlight the potential of tear EVs as a non-invasive source of biomarkers that capture retinal molecular alterations in USH1B, with applications for diagnosis, monitoring, and therapeutic development. Although this is a pilot study focused on uncovering promising biomarkers rather than establishing definitive cause–effect mechanisms, it provides a foundation for future research with larger cohorts to validate and expand these findings.

The online version contains supplementary material available at 10.1007/s00018-025-06025-9.

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