CLRN1 Variants in Müller Cells Cause Mitochondrial Dysfunction in USH3A Retinal Organoids
Rui Zhang, Xinbo Ji, Han Yu, Jingwen Xu, Yu Wang, Ping Sun, Yingxin Wang, Yao Tang, Zexin Zhan, Yichang Jiao, Didi Shan, Pengfei Lin, Dong‐dong Wang, Yuying Zhao, Xianyang Liu, Chuanzhu Yan, Jianqiao Li, Mingfeng Li, Fuchen Liu, Shengping HouABSTRACT
Background
Usher syndrome 3A (USH3A), caused by mutations in the CLRN1 gene, leads to retinitis pigmentosa and sensorineural hearing loss. While CLRN1 's role in inner ear pathology is established, its contribution to retinal degeneration remains poorly understood.
Methods
Retinal organoids derived from a USH3A patient were analyzed using single‐cell RNA sequencing and multi‐electrode array recording. CLRN1 expression was mapped in human fetal retina and organoids. We assessed the structural, transcriptional, and functional impact of CLRN1 variants on Müller cells and photoreceptors, and evaluated idebenone as a potential targeted therapy.
Results
CLRN1 was specifically expressed in Müller cells. CLRN1 variants induced severe retinal degeneration, characterized by outer nuclear layer thinning, impaired photoreceptor gene expression, activated apoptosis, and diminished electrophysiological function. Mechanistically, these variants caused mitochondrial dysfunction in Müller cells, which triggered secondary mitochondrial impairment, oxidative stress, and apoptosis in photoreceptors. Idebenone treatment partially rescued these deficits.
Conclusions
CLRN1 ‐related mitochondrial impairment in Müller cells contributes to the pathogenesis of retinitis pigmentosa in USH3A. These findings identify Müller cell mitochondrial dysfunction as a key disease mechanism and highlight potential therapeutic targets.