Ciliopathies are heterogeneous genetic diseases affecting primary cilium structure and function. Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndromes are severe ciliopathies characterized by skeletal and neurodevelopment anomalies, including polydactyly, cognitive impairment, and retinal degeneration. We describe the generation and molecular characterization of human induced pluripotent stem cell (iPSC)-derived retinal sheets (RSs) from controls, and MKS (TMEM67) and BBS (BBS10) cases. MKS and BBS RSs displayed significant common alterations in the expression of hundreds of developmental genes and members of the WNT and BMP pathways. Induction of crystallin molecular chaperones was prominent in MKS and BBS RSs suggesting a stress response to misfolded proteins. Unique to MKS photoreceptors was the presence of supernumerary centrioles and cilia, and aggregation of ciliary proteins. Unique to BBS photoreceptors was the accumulation of DNA damage and activation of the mitotic spindle checkpoint. This study reveals how combining cell reprogramming, organogenesis, and next-generation sequencing enables the elucidation of mechanisms involved in human ciliopathies.

纤毛病是影响初级纤毛结构和功能的异质遗传性疾病。 Meckel-Gruber (MKS) 和 Bardet-Biedl (BBS) 综合征是严重的纤毛病，其特征是骨骼和神经发育异常，包括多指畸形、认知障碍和视网膜变性。我们描述了对照、MKS (TMEM67) 和 BBS (BBS10) 病例中人诱导多能干细胞 (iPSC) 衍生的视网膜片 (RS) 的生成和分子特征。 MKS 和 BBS RS 在数百个发育基因以及 WNT 和 BMP 途径成员的表达中表现出显着的共同改变。晶状体蛋白分子伴侣的诱导在 MKS 和 BBS RS 中很突出，表明对错误折叠蛋白的应激反应。 MKS 光感受器的独特之处在于存在多余的中心粒和纤毛，以及纤毛蛋白的聚集。 BBS 光感受器的独特之处在于 DNA 损伤的积累和有丝分裂纺锤体检查点的激活。这项研究揭示了如何将细胞重编程、器官发生和下一代测序结合起来，阐明人类纤毛病的机制。