显性视网膜色素变性会损害光感受器发育，并表明视锥细胞参与视网膜类器官的形成。
Dominant -retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids.
作者信息
Méjécase Cécile, Zhou Ya, Owen Nicholas, Soro-Barrio Pablo, Cheloni Riccardo, Nair Neelima, Sarkar Hajrah, Toualbi Lyes, Moosajee Mariya
机构信息
Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom.
Ocular Genomics and Therapeutics, The Francis Crick Institute, London, United Kingdom.
出版信息
Front Cell Dev Biol. 2025 Apr 29;13:1511066. doi: 10.3389/fcell.2025.1511066. eCollection 2025.
INTRODUCTION
Retinal dehydrogenase 12 (RDH12) is a photoreceptor NADPH-dependent retinal reductase enzyme, converting all--retinal to all--retinol. Heterozygous variants in cause a rare autosomal dominant (AD) retinitis pigmentosa.
METHODS
As no disease models exist, we generated human induced pluripotent stem cell-derived retinal organoids (RO) from an -AD patient (with pathogenic variant c.759del, p.Phe254Leufs*24) alongside a healthy, unaffected control.
RESULTS
-AD RO exhibited correct localization of to the photoreceptor inner segments up to week 44; however, transmission electron microscopy at week 37 showed that photoreceptors were less abundant and shorter in length. Visual cone function, retinol biosynthesis, and the vitamin A pathway were also highly disrupted at week 44.
DISCUSSION
Our study is the first to describe an -AD disease model with pathology at later stages of photoreceptor differentiation, in keeping with the milder disease course seen in humans. It provides insights into the etiology and possible targets for future therapeutic development.
引言
视网膜脱氢酶12（RDH12）是一种光感受器依赖NADPH的视网膜还原酶，可将全反式视黄醛转化为全反式视黄醇。 中的杂合变异会导致一种罕见的常染色体显性（AD）色素性视网膜炎。
方法
由于不存在疾病模型，我们从一名AD患者（具有致病性变异c.759del，p.Phe254Leufs*24）以及一名健康、未受影响的对照者身上生成了人诱导多能干细胞衍生的视网膜类器官（RO）。
结果
AD RO在第44周之前视黄醛脱氢酶12在光感受器内节的定位正确；然而，第37周的透射电子显微镜显示，光感受器数量较少且长度较短。在第44周时，视锥细胞功能、视黄醇生物合成和维生素A途径也受到高度破坏。
讨论
我们的研究首次描述了一种在光感受器分化后期出现病理变化的AD疾病模型，这与人类中观察到的较轻疾病进程一致。它为病因学和未来治疗发展的可能靶点提供了见解。
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