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Background <p>Retinitis Pigmentosa (RP) is the most prevalent inherited retinal dystrophy, with more than 120 causative genes. Among them, <i>RHO</i> was the first photoreceptor gene described to harbor mutations responsible for RP. <i>RHO</i> pathogenic variants usually induce a dominant negative effect in which the accumulation of misfolded rhodopsin protein leads to ER stress, autophagy and lastly rod photoreceptor death.</p> Methods <p>We differentiated photoreceptor precursors and retinal organoids from an iPSC line of a patient carrying the Pro215Leu mutation in <i>RHO</i> gene. Both cell models were analyzed to determine their maturation, the expression and localization of <i>RHO</i> mRNA and the rhodopsin protein and the activation of autophagy or ER pathways.</p> Results <p>The Pro215Leu mutation causes rhodopsin accumulation in the soma of rod photoreceptor precursors along with a faster recycling by the proteasome. In both precursors and retinal organoids, we observed autophagy defects and late endoplasmic reticulum stress through CHOP increase.</p> Conclusions <p>Unraveling the molecular pathophysiology of these mutations is key for understanding the basis of the disease and design proper gene and cell therapies for its treatment.</p>

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Endoplasmic reticulum stress and rhodopsin accumulation in an organoid model of Retinitis Pigmentosa carrying a RHO pathogenic variant

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月14日

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  • Arnau Navinés-Ferrer,
  • Esther Pomares

摘要

Background

Retinitis Pigmentosa (RP) is the most prevalent inherited retinal dystrophy, with more than 120 causative genes. Among them, RHO was the first photoreceptor gene described to harbor mutations responsible for RP. RHO pathogenic variants usually induce a dominant negative effect in which the accumulation of misfolded rhodopsin protein leads to ER stress, autophagy and lastly rod photoreceptor death.

Methods

We differentiated photoreceptor precursors and retinal organoids from an iPSC line of a patient carrying the Pro215Leu mutation in RHO gene. Both cell models were analyzed to determine their maturation, the expression and localization of RHO mRNA and the rhodopsin protein and the activation of autophagy or ER pathways.

Results

The Pro215Leu mutation causes rhodopsin accumulation in the soma of rod photoreceptor precursors along with a faster recycling by the proteasome. In both precursors and retinal organoids, we observed autophagy defects and late endoplasmic reticulum stress through CHOP increase.

Conclusions

Unraveling the molecular pathophysiology of these mutations is key for understanding the basis of the disease and design proper gene and cell therapies for its treatment.