Cilia and Human Disease

Abstract

Cilia and centrioles are highly conserved organelles that have hundreds of proteins associated with them. Studies in mice have shown that these organelles are essential for mammalian development and mice that cannot assemble them die in utero. However, mutations in many cilia and centriole genes cause human diseases that show a great range in defects. Defects in centrioles are associated with microcephaly and mental retardation. The reduction in brain size is related to the loss of neuronal progenitor cells. Defects in centrioles may also be associated with Sjögren syndrome, an autoimmune disease, because of defects in formation of the immunological synapse. Defects that cause immotile cilia result in chronic respiratory infections, infertility, and congenital heart defects. Defects in primary cilia share various symptoms that include loss of vision, obesity, diabetes, cystic kidney disease, mental retardation, polydactyly, and short bones. Many of these diseases are associated with the transport and sorting of receptors onto the ciliary membrane for sensing the environment.

Key Concepts:

  • Cilia perform functions in many different tissues and during development.

  • Many ciliary mutations affect multiple tissues and organs.

  • Key signalling pathways require cilia.

  • Orientation of the spindle during mitosis requires functional centrioles.

Keywords: cilia; centriole; basal body; transition zone; microcephaly; autoimmune disease; cystic kidney disease; obesity; retinal degeneration; polydactyly

Figure 1.

Structure of the cilium. The cilium is a hair‐like protrusion covered by membrane with a unique content from the rest of the plasma membrane. The basal bodies, which interconvert to centrioles during mitosis, are composed of triplet microtubules that serve as a template for the axoneme. The axoneme has doublet microtubules, with motile cilia also having a central pair of microtubules not found in primary cilia. The dynein arms and radial spokes are required for the motility of cilia. The nexin links connect the doublet microtubules to each other and prevent the microtubules from sliding past each other. Vesicles destined for the cilium are sorted in the Golgi complex and the BBsome is thought to help proteins and vesicles enter the cilium. The transition fibres are attachments between the basal body and the plasma membrane and act as a sieve to prevent passive diffusion of proteins between the cytoplasm and the cilium. Cargo is transported to the tip of the cilium via anterograde transport by IFT complex B. Cargo returns to the cytoplasm by retrograde transport of IFT complex A. The diseases and syndromes described in the article have defects in the basal body, cilium, or the proteins needed to make these structures.

Figure 2.

Ciliopathies have a broad spectrum of symptoms. The photoreceptor is a specialised cilium and many of the ciliopathies have vision or other eye defects. The severity of eye problems is indicated by colour with the most severe in dark purple and least severe in light purple. Both the kidneys and liver are commonly affected. Bone defects manifest as either shortened long bones or polydactyly. Defects in motile cilia can lead to increased incidence of respiratory tract infections. Laterality defects (situs inversus) where the organs placement has switched sides, is the result of motile cilia of the embryonic node not beating properly. Defects in cilia found in the brain can result in mental retardation or brain malformations. Obesity is also associated with ciliopathies, although the connection between obesity and cilia is not clear. Many of the ciliopathies share symptoms and many of the implicated genes are mutated in multiple disorders. Adapted from Mockel et al. with permission from Elsevier.

Figure 3.

Spindle position controls neural differentiation and development of microcephaly. Neuroepithelial progenitors in normal brains divide both symmetrically (top) and asymmetrically (bottom). The result is an increase in the progenitor pool and production of differentiating cells. In microcephaly, there is a loss of symmetric cell division and a corresponding loss of neuroepithelial progenitors leading to small brains (Konno et al., ).

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Albee, Alison J, and Dutcher, Susan K(Jul 2012) Cilia and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022544]