Nonsense Mutation in USH2A Exon-13 Activates the Innate Immune Response in Müller Glial Cells

TL;DR

A mutation in the USH2A gene causes retinal degeneration by triggering immune responses in glial cells, not directly harming photoreceptors.

Contribution

This study reveals that Müller glial cells, not photoreceptors, are primarily affected by a USH2A mutation, suggesting new therapeutic targets.

Findings

A nonsense mutation in USH2A exon-13 disrupts usherin localization but spares photoreceptor development.

Müller glial cells show significant transcriptional changes in translation, immune response, and endolysosomal systems.

The findings suggest Müller glial cells may drive disease progression in Usher syndrome.

Abstract

Pathological USH2A mutations cause Usher syndrome type II, characterized by progressive retinitis pigmentosa and hearing and balance impairment. This study aims to investigate the cellular mechanisms underlying USH2A-related retinal degeneration using human induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant transcriptional changes in Müller glial cells (MGCs), suggestive of disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major transcriptional changes, potentially contributing to the disease progression and therefore shedding light on potential alternative therapeutic targets.

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