On the Wrong Track: Alterations of Ciliary Transport in Inherited Retinal Dystrophies

Abstract

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.

A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies

“…As occurs with mutations in ~30 ciliary genes 35 , the manifestation of extra-ocular features can vary from patient to patient 36 , 37 , depending on the severity of the mutations 36 , 37 , the genetic background 38 , the presence of genetic modifiers 39 or tissue-specific alternative splicing 40 , among other factors. Interestingly, depending on the mutation, the same ciliary 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 41 .…”

Specialization of the photoreceptor transcriptome bySrrm3-dependent microexons is required for outer segment maintenance and vision

“…Altogether, these functions suggest that RetMICs enable a unique proteome specialization that is necessary for proper development and functioning of the OS, the highly modified cilium of PRs. Given the unusually high demand for vesicle formation, transport, and recycling in the OS 4 , the specific modifications introduced by RetMICs in otherwise ubiquitous trafficking and ciliary machinery may help meet this high demand by promoting interactions with PR-specific substrates and/or facilitating unique catalytic properties not required (or even detrimental) in other cell types. In line with this idea, depletion of srrm3 caused severe malformation of the OS and vesicle accumulation, leading to PR degeneration and impaired visual function.…”

“…OSs are filled with densely packed and organized membranous disks that undergo rapid and extensive renewal to guarantee the proper supply of proteins such as rhodopsin, cone opsins and other visual pigments 3 . The delivery of those components from the Golgi to the ciliary tip and back is sustained by a high-capacity vesicle-mediated transport system, carried along the ciliary axoneme 4 . Consequently, multiple genes whose mutations are known to cause PR degeneration leading to syndromic or non-syndromic retinal ciliopathies encode for proteins involved in OS vesicular transport 4,5 .…”

“…The delivery of those components from the Golgi to the ciliary tip and back is sustained by a high-capacity vesicle-mediated transport system, carried along the ciliary axoneme 4 . Consequently, multiple genes whose mutations are known to cause PR degeneration leading to syndromic or non-syndromic retinal ciliopathies encode for proteins involved in OS vesicular transport 4,5 .…”

A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

“…ARL3 encodes ADP-ribosylation factor, (Arf)-like protein 3. This soluble small GTPase has been localized to photoreceptors, and mutations in the ARL3 gene are considered to cause retinal ciliopathy (Frederick et al, 2020;Sánchez-Bellver et al, 2021).…”