2026-07-09 | Characterization of Rcbtb1 Knockout Mice and Evaluation of AAV2-RCBTB1 Gene Replacement Therapy.

Biallelic pathogenic variants in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene cause an adult-onset retinal dystrophy. Here, we generated a knockout mouse model of RCBTB1 deficiency for the evaluation of RCBTB1 gene therapy. Rcbtb1-knockout (KO) mice were generated with a homozygous deletion removing exons 2 and 3 of Rcbtb1. Wild-type (WT) and Rcbtb1-KO mice were assessed by optical coherence tomography and electroretinography at 3, 8, and 14 months of age. Retinal ultrastructure was assessed by transmission electron microscopy. Subretinal injections of adeno-associated virus 2 (AAV2)-RCBTB1 or AAV2-enhanced green fluorescent protein (EGFP) vector were performed at 2 months, and mice were analyzed at 8 months. Retinal gene expression was assessed by quantitative PCR and immunohistochemistry. Retinal Rcbtb1 expression was absent in Rcbtb1-KO mice. Eight-month-old Rcbtb1-KO mice showed reduced outer retinal thickness compared with WT mice. Ultrastructural analysis demonstrated increased mitochondrial damage in retinal pigment epithelial cells and increased frequencies of mitochondria with oxidative inclusions in photoreceptor inner segments in 8-month-old Rcbtb1-KO mice. Degenerating retinal pigment epithelium (RPE) and photoreceptors were observed in Rcbtb1-KO mice. Bruch's membrane appeared thicker in Rcbtb1-KO mice and contained druse-like deposits. Treatment with AAV2-RCBTB1 induced sustained RCBTB1 expression and preserved outer retinal thickness in 8-month-old Rcbtb1-KO mice. Rcbtb1-KO mice showed accelerated outer retinal thinning, increased mitochondrial damage in the RPE, and photoreceptor apoptosis. AAV2-RCBTB1 vectors induced long-term retinal expression of RCBTB1 and prevented retinal thinning in Rcbtb1-KO mice. Rcbtb1-KO mice provide a useful animal model for modeling RCBTB1 deficiency and preclinical screening of novel treatments.

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2026-07-06 | Bardet-Biedl syndrome in a Chinese patient with a novel homozygous BBS5 variant from paternal uniparental disomy.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive genetic disorder with multi-systemic symptoms, including polydactyly, obesity, renal anomalies, retinal dystrophy, and cognitive impairment. Our study reported a previously unreported BBS5 homozygous variant in a Chinese patient with BBS from paternal uniparental disomy. A comprehensive ophthalmologic examination was conducted. Whole-exome sequencing and Sanger sequencing were utilized to detect pathogenic variants. Protein structure prediction and multiple sequence alignment were performed. An 18-year-old female presented with blurry vision and night blindness since childhood. Upon conducting a general assessment, polydactyly, obesity and learning disability were also identified. Ophthalmologic examination revealed severe retinal degeneration. Whole-exome and Sanger sequencing detected a homozygous BBS5 variant (NM_152384.3: exon 3: c.185del; p.L62Wfs*16), with the homozygosity from paternal uniparental disomy. The protein structure prediction showed substantial deletions of amino acid segments caused by the variant. Multiple sequence alignment indicated that the amino acids corresponding to the variant were in a highly conserved region of the BBS5 protein, underscoring their essential role in maintaining protein function. Our study identified a novel homozygous BBS5 variant from paternal uniparental disomy. These findings expand the genotypic and phenotypic spectrum of Bardet-Biedl syndrome.

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2026-06-29 | Retinal network dysfunction precedes structural degeneration in severe GUCA1A cone-rod dystrophy

Abstract Autosomal dominant cone-rod dystrophy caused by GUCA1A mutations is generally viewed as a disorder of phototransduction, yet the mechanisms linking photoreceptor dysfunction to progressive vision loss remain unclear. Here, using a knock-in mouse carrying the severe GCAP1 p.(E111V) variant, we show that retinal network dysfunction precedes structural degeneration. Mutant mice exhibited delayed rod photoresponses, increased light sensitivity, selective visuospatial deficits, and progressive impairment of visually evoked responses in the superior colliculus and visual cortex, demonstrating propagation of functional deficits beyond photoreceptors. Transcriptomic and ultrastructural analyses revealed early synaptic, mitochondrial and inflammatory alterations despite largely preserved retinal architecture. Acute ex vivo delivery of recombinant wild-type GCAP1 partially restored mutant rod photoresponse kinetics, indicating that these early functional deficits remain biochemically modifiable. These findings redefine severe GUCA1A -associated disease as a progressive disorder of retinal network function, identifying an early therapeutic window before structural degeneration. One-Sentence Summary Visual function breaks down long before photoreceptors are lost, opening an early window for intervention.

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