PDF(Pubmed)
Abstract：
Mutations in the IQ calmodulin-binding motif containing B1 (IQCB1)/NPHP5 gene encoding the ciliary protein nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction in Senior-Løken syndrome. For in vitro disease modeling, we obtained dermal fibroblasts from patients with NPHP5-LCA that were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into retinal pigment epithelium (RPE) and retinal organoids. Patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. Disease phenotype in NPHP5-LCA retinal organoids could be rescued by adeno-associated virus (AAV)-mediated IQCB1/NPHP5 gene augmentation therapy. Our studies thus establish a human disease model and a path for treatment of NPHP5-LCA.
摘要：
包含B1（IQCB1）/NPHP5基因的IQ钙调蛋白结合基序中的突变编码睫状蛋白肾囊蛋白5，可导致早发性致盲疾病Leber先天性黑蒙（LCA），老年-洛肯综合征的肾功能不全。对于体外疾病建模，我们从NPHP5-LCA患者中获得真皮成纤维细胞,这些成纤维细胞重编程为诱导多能干细胞(iPSCs),并分化成视网膜色素上皮(RPE)和视网膜类器官.患者成纤维细胞和RPE显示异常细长的睫状轴突。类器官显示外节结构发育受损，是改性的初级纤毛，和视觉色素在感光细胞中的错误定位。所有患者来源的细胞显示CEP290蛋白水平降低，与NPHP5相互作用的关键纤毛过渡区成分，为异常纤毛门控和货物运输提供了合理的机制。NPHP5-LCA视网膜类器官的疾病表型可以通过腺相关病毒（AAV）介导的IQCB1/NPHP5基因增强疗法来挽救。因此，我们的研究建立了人类疾病模型和治疗NPHP5-LCA的途径。
