Navinés-Ferrer Arnau, Pomares Esther
Departament de Genètica, IMO Grupo Miranza, Barcelona, Spain.
Stem Cell Res Ther. 2025 Feb 14;16(1):71. doi: 10.1186/s13287-025-04199-4.
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.
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.
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.
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.
视网膜色素变性（RP）是最常见的遗传性视网膜营养不良，有120多个致病基因。其中，RHO是首个被描述携带导致RP突变的光感受器基因。RHO致病变体通常会诱导显性负效应，其中错误折叠的视紫红质蛋白的积累会导致内质网应激、自噬，最终导致视杆光感受器死亡。
我们从一名携带RHO基因Pro215Leu突变的患者的诱导多能干细胞系中分化出光感受器前体细胞和视网膜类器官。对这两种细胞模型进行分析，以确定它们的成熟度、RHO mRNA和视紫红质蛋白的表达及定位，以及自噬或内质网途径的激活情况。
Pro215Leu突变导致视紫红质在视杆光感受器前体细胞的胞体中积累，同时蛋白酶体的再循环加快。在光感受器前体细胞和视网膜类器官中，我们都观察到自噬缺陷和通过CHOP增加所反映的晚期内质网应激。
阐明这些突变的分子病理生理学是理解该疾病基础并设计合适的基因和细胞疗法进行治疗的关键。
