Ciliopathies: an expanding disease spectrum

Abstract

Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that include characteristically, retinal degeneration, renal disease and cerebral anomalies. Additional manifestations include congenital fibrocystic diseases of the liver, diabetes, obesity and skeletal dysplasias. Ciliopathic features have been associated with mutations in over 40 genes to date. However, with over 1,000 polypeptides currently identified within the ciliary proteome, several other disorders associated with this constellation of clinical features will likely be ascribed to mutations in other ciliary genes. The mechanisms underlying many of the disease phenotypes associated with ciliary dysfunction have yet to be fully elucidated. Several elegant studies have crucially demonstrated the dynamic ciliary localisation of components of the Hedgehog and Wnt signalling pathways during signal transduction. Given the critical role of the cilium in transducing "outside-in" signals, it is not surprising therefore, that the disease phenotypes consequent to ciliary dysfunction are a manifestation of aberrant signal transduction. Further investigation is now needed to explore the developmental and physiological roles of aberrant signal transduction in the manifestation of ciliopathy phenotypes. Utilisation of conditional and inducible murine models to delete or overexpress individual ciliary genes in a spatiotemporal and organ/cell-specific manner should help clarify some of the functional roles of ciliary proteins in the manifestation of phenotypic features.

Fig. 1

The primary cilium. a, b Cilia are cytoplasmic extensions projecting from the cell surface and composed of a microtubular-based ciliary axoneme. The transition zone is where the microtubules are reorganised into pairs and anchor the pairs to the membrane. Within this region, proteins involved in trafficking along the axoneme also accumulate. b, c Schematic of a transverse section through c the motile cilium, showing the radial spoke proteins and outer dynein arms, and d the non-motile cilium

Fig. 2

Intraflagellar transport. Elongation of the axoneme at the distal tip relies on intraflagellar transport (IFT). Anterograde IFT is mediated by kinesin II motors along with axonemal precursors, while retrograde IFT is mediated by a dynein motor. IFT Type A complexes are linked to retrograde transport and IFT Type B complexes are linked to anterograde transport

Fig. 3

The BBSome and vesicular trafficking to the primary cilium. The BBSome is a multi-protein complex comprising BBS proteins (BBS 1, 2, 4, 5, 7, 8 and 9) that localises predominantly at the ciliary base and mediates vesicular transport to the cilium

Fig. 4

Clinical features of ciliopathies. a Renal ultrasound demonstrating multiple cysts distributed within the renal parenchyma (white arrow). b Renal biopsy demonstrating cystic tubular dilation and interstitial fibrosis characteristic of nephronophthisis (NPHP; black arrow). c Funduscopy of a patient with Bardet–Biedl syndrome demonstrating peripheral pigmentary changes in the retina. d Cranial MRI of a patient with Joubert syndrome demonstrating characteristic “molar tooth” sign (white arrow) as a result of cerebellar vermis hypoplasia

Fig. 5

Skeletal manifestations of ciliopathies. a A Jeune asphyxiating thoracic dystrophy (JATD) patient with a narrow thorax. b CT of same patient demonstrating short ribs and narrow thoracic cage. c Upper limb radiography of a patient with Mainzer–Saldino syndrome demonstrating acromesomelic shortening with irregular metaphyses and cone-shaped epiphyses