Rusterholz Tamara D S, Hofmann Claudia, Bachmann-Gagescu Ruxandra
Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
Front Genet. 2022 Jun 30;13:939527. doi: 10.3389/fgene.2022.939527. eCollection 2022.
Cilia are quasi-ubiquitous microtubule-based sensory organelles, which play vital roles in signal transduction during development and cell homeostasis. Dysfunction of cilia leads to a group of Mendelian disorders called ciliopathies, divided into different diagnoses according to clinical phenotype constellation and genetic causes. Joubert syndrome (JBTS) is a prototypical ciliopathy defined by a diagnostic cerebellar and brain stem malformation termed the "Molar Tooth Sign" (MTS), in addition to which patients display variable combinations of typical ciliopathy phenotypes such as retinal dystrophy, fibrocystic renal disease, polydactyly or skeletal dystrophy. Like most ciliopathies, JBTS is genetically highly heterogeneous with ∼40 associated genes. Zebrafish are widely used to model ciliopathies given the high conservation of ciliary genes and the variety of specialized cilia types similar to humans. In this review, we compare different existing JBTS zebrafish models with each other and describe their contributions to our understanding of JBTS pathomechanism. We find that retinal dystrophy, which is the most investigated ciliopathy phenotype in zebrafish ciliopathy models, is caused by distinct mechanisms according to the affected gene. Beyond this, differences in phenotypes in other organs observed between different JBTS-mutant models suggest tissue-specific roles for proteins implicated in JBTS. Unfortunately, the lack of systematic assessment of ciliopathy phenotypes in the mutants described in the literature currently limits the conclusions that can be drawn from these comparisons. In the future, the numerous existing JBTS zebrafish models represent a valuable resource that can be leveraged in order to gain further insights into ciliary function, pathomechanisms underlying ciliopathy phenotypes and to develop treatment strategies using small molecules.
纤毛是几乎普遍存在的基于微管的感觉细胞器，在发育和细胞内稳态过程中的信号转导中发挥着至关重要的作用。纤毛功能障碍会导致一组称为纤毛病的孟德尔疾病，根据临床表型组合和遗传原因分为不同的诊断类型。Joubert综合征（JBTS）是一种典型的纤毛病，其定义为一种诊断性的小脑和脑干畸形，称为“磨牙征”（MTS），除此之外，患者还表现出典型纤毛病表型的不同组合，如视网膜营养不良、纤维囊性肾病、多指畸形或骨骼营养不良。与大多数纤毛病一样，JBTS在遗传上高度异质，有大约40个相关基因。鉴于纤毛基因的高度保守性以及与人类相似的各种特殊纤毛类型，斑马鱼被广泛用于建立纤毛病模型。在这篇综述中，我们比较了现有的不同JBTS斑马鱼模型，并描述了它们对我们理解JBTS发病机制的贡献。我们发现，视网膜营养不良是斑马鱼纤毛病模型中研究最多的纤毛病表型，根据受影响的基因，其由不同的机制引起。除此之外，在不同的JBTS突变模型之间观察到的其他器官表型差异表明，与JBTS相关的蛋白质具有组织特异性作用。不幸的是，目前文献中描述的突变体中纤毛病表型缺乏系统评估，限制了从这些比较中得出的结论。未来，众多现有的JBTS斑马鱼模型是一种宝贵的资源，可以利用它们进一步深入了解纤毛功能、纤毛病表型的发病机制，并开发使用小分子的治疗策略。
