2026-07-10 | Single-cell analysis reveals impaired Müller glia-mediated intercellular communication and photoreceptor pathology in USH1C retinal organoids.
Usher syndrome type 1, caused by pathogenic variants in the USH1C gene, leads to congenital deafness and progressive retinal degeneration resulting in vision loss. While auditory deficits can be compensated by cochlea implants and hearing aids, no treatment exists to prevent retinal degeneration. Here, we generated retinal organoids from induced pluripotent stem cells of two USH1C patients to elucidate the cellular and molecular mechanisms driving ocular pathogenesis. Single-cell RNA sequencing of healthy and USH1C retinal organoids identified differential expression of genes related to phototransduction in photoreceptors, as well as alterations in cell adhesion and canonical Wnt signaling in Müller glia cells. Analysis of intercellular communication revealed an overall reduced signaling efficiency, particularly affecting Müller glia-mediated retinal adhesion processes. Morphological characterization of organoids confirmed transcriptome changes by showing degeneration of the outer limiting membrane and loss of adherens junction architecture. Moreover, photoreceptors revealed increased levels of apoptosis, as well as morphological and functional changes related to phototransduction. Our results demonstrate that disruption of Müller glia signaling contributes to an overall loss of retinal integrity, providing novel insights into USH1C pathogenesis and offering targets for therapeutic interventions.
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2026-07-02 | Müller Glia-Exclusive CLRN1 Expression Drives Non-Cell-Autonomous Photoreceptor Degeneration in Usher Syndrome Type 3A.
Usher syndrome type 3A (USH3A), caused by CLRN1 mutations, leads to progressive deaf-blindness. Although CLRN1 expression has been localized to Müller glia (MG), the pathogenic mechanisms linking glial CLRN1 deficiency to photoreceptor death remain undefined. We utilized a novel large-animal model to elucidate cell-type-specific pathogenesis at single-nucleus resolution. CLRN1-/- rabbits were generated via CRISPR/Cas9. Retinal phenotyping included longitudinal optical coherence tomography (OCT), electroretinography (ERG), and histology for up to 3 years. Single-nucleus RNA sequencing (snRNA-seq) was performed at a pre-symptomatic stage (10 months, n = 3/genotype). Differentially expressed genes (DEGs) were identified using pseudobulk DESeq2 and validated via immunofluorescence. CLRN1-/- rabbits exhibited progressive outer nuclear layer thinning and delayed ERG responses starting after 20 months, mimicking human clinical kinetics. The snRNA-seq revealed that CLRN1 is exclusively expressed in a discrete subset (∼24%) of MG. Mutant MG exhibited transcriptomic downregulation of the adherens junction component CTNNA2, which was validated at the protein level by immunofluorescence staining. Photoreceptors exhibit extensive non-cell-autonomous dysregulation (232 rod and 68 cone DEGs) characterized by loss of the cone synaptic organizer TENM2 and rod-specific splicing dysregulation (CWF19L2). Concurrently, inner retinal neurons mounted a robust proteostatic response via HSP90 family upregulation (HSP90AB1, HSP90AA1, HSP90B1), a defensive signature absent in vulnerable photoreceptors. Our findings suggest an "anchor-shield" mechanism: MG CLRN1 loss compromises the outer limiting membrane (OLM) adhesion complex ("anchor"), and photoreceptors lack the proteostatic response ("shield") seen in resilient inner neurons. Restoring CLRN1 in Müller glia or implementing photoreceptor neuroprotection represents promising therapeutic strategies for USH3A.
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2026-06-11 | Multimodal imaging and intravitreal faricimab for polypoidal choroidal vasculopathy associated with a choroidal nevus in genetically confirmed Usher syndrome type 2: a case report.
Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa (RP), sensorineural hearing loss, and vestibular dysfunction. Polypoidal choroidal vasculopathy (PCV) is characterized by branching neovascular networks and polypoidal lesions. While typically classified within the pachychoroid spectrum, PCV can also manifest in eyes without choroidal thickening. Conversely, RP is usually associated with choroidal thinning, which may lead to underdiagnosis of PCV. To the best of our knowledge, PCV has not previously been reported in patients with Usher syndrome. Here, we present the first genetically confirmed case of Usher syndrome type 2 complicated by PCV that was successfully managed with intravitreal faricimab. A 63-year-old man presented with night blindness. The diagnosis of Usher syndrome type 2 was confirmed based on bilateral RP features, moderate sensorineural hearing loss, and two pathogenic USH2A variants. Six years after the initial diagnosis, the patient developed visual disturbance in the left eye, with the best-corrected visual acuity (BCVA) declining to 20/80. Multimodal imaging, including spectral-domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, and swept-source optical coherence tomography angiography, confirmed the diagnosis of PCV. An amelanotic choroidal nevus was also identified on SD-OCT. After five intravitreal faricimab injections, the BCVA improved to 20/30, with a 75% reduction in pigment epithelial detachment height and complete subretinal fluid resolution without adverse effects. To our knowledge, this is the first reported case of PCV associated with a choroidal nevus in a patient with genetically confirmed Usher syndrome type 2. PCV should not be excluded in patients with RP despite characteristic choroidal thinning. Intravitreal faricimab was effective and well-tolerated, suggesting its therapeutic potential in such cases.
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