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Loss of ABCA4 from photoreceptor discs triggers changes in glial cell homeostasis

ABSTRACT: Loss-of-function mutations in the ABCA4 gene cause Stargardt disease (STGD1), the most common inherited macular dystrophy leading to progressive central vision loss. Here, we generated hiPSC-derived retinal organoids harboring a premature stop codon in exon-24 of ABCA4 to investigate pathogenic mechanisms in a human model. Immunofluorescence analysis revealed the absence of ABCA4 protein in the mutant photoreceptor outer segment discs, while single-cell RNA sequencing detected no major transcriptional alterations in rods and cones. Unexpectedly, differential gene expression and pathway enrichment analyses of Müller glial cells (MGCs) and astrocytes highlighted disruption of neuronal development, microenvironment of glial cells, intercellular communication, and programmed cell death pathways. These findings suggest that ABCA4 might be involved in the regulation of the retinal microenvironment homeostasis, raising the possibility that MGCs and astrocytes contribute to Stargardt disease development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326273 | GEO | 2026/09/09

REPOSITORIES: GEO

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Project description:Stargardt disease (STGD1) is an inherited retinopathy affecting approximately 1:8,000 individuals. It is characterised by biallelic mutations in ABCA4, and encodes a vital protein for the recycling of retinaldehyde in the retina. Despite its prevalence and impact, there are currently no treatments available for this condition. Furthermore, 35% of STGD1 cases remain genetically unsolved. Efforts have been directed towards comprehending the fundamental disease mechanisms and identifying all disease-causing variants in the extensive 150kb gene, to better aid with the development of effective therapeutic strategies. In this study, we generated iPSC lines from two monoallelic (PT1 & PT2), late onset STGD1 cases with the heterozygous complex allele - c.[5461-10T>C;5603A>T]. We differentiated these cells alongside a biallelic affected control (AC) - c.4892T>C, and c.4539+2001G>A, to retinal organoids (ROs) allowing us to investigate cellular and molecular characteristics associated with STGD1. We hypothesized that the missing inheritance in our monoallelic cases is due to an RNA defect. Consequently, we utilised a myriad of sequencing strategies including WGS, single-cell RNA sequencing (scRNAseq) and long-read RNA sequencing (LRS) to address this. ROs were grown for 230 days and developed all key retinal neurons with photoreceptor outer segments capable of ABCA4 expression. We observed patient-specific disruption to lamination with OPN1MW/LW+ cone photoreceptor retention in the RO centre during differentiation. Retention was more severe in the AC case affecting both cones and rods, suggesting a genotype/phenotype correlation. scRNAseq suggests retention may be due to the induction of apoptosis in photoreceptors. WGS successfully identified the missing alleles in both cases; PT1 reported c. 5603A>T in homozygous state and PT2 uncovered a rare hypomorph - c.4865T>C. Furthermore, ROs were able to recapitulate the retina-specific splicing defect in PT1 as shown by LRS data. Collectively, these results highlight the suitability of ROs in STGD1 modelling. Their ability to display genotype-phenotype correlations enhances their utility as a platform for therapeutic development. Importantly, both PT1 and PT2 cases were genetically resolved in this study, providing two more individuals their confirmed genetic diagnosis.

			Action	DRS
		Other
	GSE326273_barcodes.tsv.gz	Tabular
	GSE326273_feature_reference.csv.gz	Csv
	GSE326273_features.tsv.gz	Tabular
	GSE326273_matrix.mtx.gz	Other

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Loss of ABCA4 from photoreceptor discs triggers changes in glial cell homeostasis

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