Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA 6009, Australia.
Ocular Tissue Engineering Laboratory, Lions Eye Institute, Nedlands, WA 6009, Australia.
Genes (Basel). 2021 Sep 28;12(10):1542. doi: 10.3390/genes12101542.
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between polymorphism, repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized and expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy repeat in the promoter, while 3/5 NPCs carried a 4-copy repeat. The rs4806718 genotype did not correlate with disease penetrance. expression declined with age in adult cadaveric retina. and expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy repeat, but not with polymorphisms.
色素性视网膜炎 11 型（RP11）是由 中的显性突变引起的，然而，相当一部分突变携带者不会发展为视网膜病变。在这里，我们研究了 RP11 患者和非穿透性携带者（NPCs）中 多态性、 重复拷贝数与疾病外显率之间的关系。我们进一步描述了来自携带 c.1205C>T 变异的一个家族的 8 个 RP11 患者和 1 个 NPC 的成纤维细胞中的 和 表达。从 RP11 患者、NPC 和对照受试者的诱导多能干细胞中分化出视网膜类器官（ROs）和视网膜色素上皮（RPE）。所有 RP11 患者的 启动子中均为 3 拷贝的 重复纯合子，而 5 个 NPC 中有 3 个携带 4 拷贝的 重复。 rs4806718 基因型与疾病外显率无关。成人尸体视网膜中 表达随年龄增长而下降。与对照相比，RP11 成纤维细胞、RO 和 RPE 中的 和 表达减少。与对照相比，RP11 和 NPC RPE 均显示初级纤毛缩短，但 NPC RPE 单层中存在具有正常纤毛长度的细胞亚群。我们的结果表明，RP11 非穿透性与 4 拷贝 重复的遗传有关，但与 多态性无关。
