Sánchez-Bellver Laura, Toulis Vasileios, Marfany Gemma
Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Spain.
Institute of Biomedicine (IBUB-IRSJD), Universitat de Barcelona, Barcelona, Spain.
Front Cell Dev Biol. 2021 Mar 5;9:623734. doi: 10.3389/fcell.2021.623734. eCollection 2021.
Ciliopathies are a group of heterogeneous inherited disorders associated with dysfunction of the cilium, a ubiquitous microtubule-based organelle involved in a broad range of cellular functions. Most ciliopathies are syndromic, since several organs whose cells produce a cilium, such as the retina, cochlea or kidney, are affected by mutations in ciliary-related genes. In the retina, photoreceptor cells present a highly specialized neurosensory cilium, the outer segment, stacked with membranous disks where photoreception and phototransduction occurs. The daily renewal of the more distal disks is a unique characteristic of photoreceptor outer segments, resulting in an elevated protein demand. All components necessary for outer segment formation, maintenance and function have to be transported from the photoreceptor inner segment, where synthesis occurs, to the cilium. Therefore, efficient transport of selected proteins is critical for photoreceptor ciliogenesis and function, and any alteration in either cargo delivery to the cilium or intraciliary trafficking compromises photoreceptor survival and leads to retinal degeneration. To date, mutations in more than 100 ciliary genes have been associated with retinal dystrophies, accounting for almost 25% of these inherited rare diseases. Interestingly, not all mutations in ciliary genes that cause retinal degeneration are also involved in pleiotropic pathologies in other ciliated organs. Depending on the mutation, the same gene can cause syndromic or non-syndromic retinopathies, thus emphasizing the highly refined specialization of the photoreceptor neurosensory cilia, and raising the possibility of photoreceptor-specific molecular mechanisms underlying common ciliary functions such as ciliary transport. In this review, we will focus on ciliary transport in photoreceptor cells and discuss the molecular complexity underpinning retinal ciliopathies, with a special emphasis on ciliary genes that, when mutated, cause either syndromic or non-syndromic retinal ciliopathies.
纤毛病是一组异质性遗传性疾病，与纤毛功能障碍相关，纤毛是一种普遍存在的基于微管的细胞器，参与广泛的细胞功能。大多数纤毛病是综合征性的，因为几个其细胞产生纤毛的器官，如视网膜、耳蜗或肾脏，会受到纤毛相关基因突变的影响。在视网膜中，光感受器细胞具有高度特化的神经感觉纤毛，即外段，外段堆叠着发生光感受和光转导的膜盘。更远端膜盘的每日更新是光感受器外段的一个独特特征，导致对蛋白质的需求增加。外段形成、维持和功能所需的所有成分都必须从发生合成的光感受器内段运输到纤毛。因此，选定蛋白质的有效运输对于光感受器纤毛发生和功能至关重要，纤毛货物递送或纤毛内运输的任何改变都会损害光感受器存活并导致视网膜变性。迄今为止，超过100个纤毛基因的突变与视网膜营养不良有关，占这些遗传性罕见疾病的近25%。有趣的是，并非所有导致视网膜变性的纤毛基因突变也参与其他有纤毛器官的多效性病理。根据突变情况，同一基因可导致综合征性或非综合征性视网膜病变，从而强调了光感受器神经感觉纤毛的高度精细特化，并增加了常见纤毛功能（如纤毛运输）背后存在光感受器特异性分子机制的可能性。在本综述中，我们将重点关注光感受器细胞中的纤毛运输，并讨论视网膜纤毛病背后的分子复杂性，特别强调那些突变时会导致综合征性或非综合征性视网膜纤毛病变的纤毛基因。
