Human Cilia Disease
Cilia are ubiquitous hair-like organelles that form specialised cell compartments, extending out from the surface of most cells in the body with an internal microtubular axoneme scaffold surrounded by a unique ciliary membrane. Distinct cilia types perform a diverse range of functions. Cilia present in the early embryo and later on in specialised epithelia are motile, using a system of internal dynein motors to move fluids, gametes and particles in the airways, brain and reproductive system. Widely distributed nonmotile primary cilia are signal transduction centres that regulate important cell signalling pathways (e.g. Hedgehog, Wnt, PDGFRα) through the sequestering and release of cell signalling machinery. They have mechano/photo/osmo-sensing functions, communicating signals between the cell and its extracellular environment. Fitting with these essential roles, genetic mutations affecting ciliary formation or function result in a diverse and defined set of clinical features known as ciliopathies. Ciliopathy diseases are inherited in families and may cause disease in at least 1 per 2,000 people. By acting as a scaffold for many important cellular functions, cilia are also likely to be important in diseases affecting ciliated tissues caused by what initially appear to be unrelated genetic or environmental insults (e.g. cystic fibrosis, osteoarthritis).
Ciliopathies provide a unique opportunity to understand fundamental principles that shape clinical outcomes in genetic disease. Ciliopathies are one of the largest categories of heritable disease, with over 100 genes having been found to be mutated in these conditions, including many genes discovered by researchers within the Cilia Disorders Section. We know the crystal structures of many of these components and we have a landscape of protein-protein interactions connecting them. We are beginning to understand how transport of proteins within cilia are important for proper cellular homeostasis and we know how certain tissues such as the limbs, eyes and kidneys become diseased when these processes go wrong. As such, we can begin to investigate mechanisms that generate diversity among patients with mutations in the same genes, opening up new avenues for treatment.
Broadly, genes mutated in ciliopathies encode core ciliary transport (i.e. intraflagellar transport) or motility (i.e. ultrastructural components) complexes, as well as accessory proteins such as ciliary vesicle transport proteins and channel proteins associated with mucocilliary membranes. These general categories represent the four areas that the section particularly focuses on, reflected by the diseases that they cause – skeletal ciliopathies, primary ciliary dyskinesia, Bardet-Biedl syndrome and cystic fibrosis.
Our research combines gene discovery with basic science investigations and development of new treatments for ciliopathies. Important basic science questions include the following:
How do stochastic processes in relation to genetic threshold effects account for clinical variability and incomplete penetrance of complex morphological traits?
How are motile and primary cilia assembled by vesicle transport and chaperone complexes?
What cell types and molecular mechanisms underlie individual clinical features in ciliopathies, including cognitive impairment, obesity, skeletal malformations and retinal degeneration?
Can we treat selected ciliopathies – including cystic fibrosis, blindness and craniosynostosis – using gene-editing, gene-replacement therapy or drug repurposing?