Nonsense Mutation in USH2A Exon-13 Activates the Innate Immune Response in Müller Glial Cells
Authors:
- Rossella ValenzanoRVRossella Valenzano
- Xuefei LuXLXuefei Lu
- Andrew McDonaldAMAndrew McDonald
- Ioannis MoustakasIMIoannis Moustakas
- Roberta MenafraRMRoberta Menafra
- Aat A. MulderAMAat A. Mulder
- Roman I. KoningRKRoman I. Koning
- Susan L. KloetSKSusan L. Kloet
- Jun YangJYJun Yang
- Hailiang MeiHMHailiang Mei
- Jan WijnholdsJan Wijnholds
Open Access
- 7 February 2026
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 27 (4) , 1636
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.Keywords
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Funding Information
- Dutch blindness funds (Uitzicht 2021-11)
- Dutch blindness funds (Uitzicht 2023-05)
- Stichting Ushersyndroom (Uitzicht 2021-11)
- Stichting Ushersyndroom (Uitzicht 2023-05)
- Rotterdamse Stichting Blindenbelangen (Uitzicht 2021-11)
- Landelijke Stichting voor Blinden en Slechtzienden (Uitzicht 2021-11)
- Landelijke Stichting voor Blinden en Slechtzienden (Uitzicht 2023-05)
- Stichting Blindenhulp (Uitzicht 2021-11)
- Stichting Oogfonds (Uitzicht 2023-05)
- Stichting Retina Fonds (Uitzicht 2023-05)
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