We use human genetics and functional studies in cells, ciliate organisms and other in vivo models to understand the molecular genetic basis of ciliopathies, with particular focus on the motile ciliopathies (primary ciliary dyskinesia) and skeletal ciliopathies (Jeune syndrome, short rib thoracic dysplasias). Human cilia and sperm play diverse roles in many processes essential to normal development and ciliopathies are an expanding group of more than 20 different human genetic disorders. Motile cilia dysfunction is associated with chronic respiratory disease and laterality and fertility defects. Dysfunction of primary (sensory) cilia, which play a role in a number of critical signalling pathways, is associated with severe developmental conditions for example chondrodysplasia, retinal degeneration and cystic kidney disease. Mutations in ciliary proteins thus underlie a wide range of complex, multisystem ciliopathy syndromes and these can individually be rare, but they collectively represent a significant health burden as they are estimated to affect 1 in 1,000 individuals.

My group's work has helped to determine novel causes of skeletal ciliopathies where restricted bone growth and multiorgan failure is often lethal. We have elucidated a cellular network of over 50 proteins essential for ciliated airway epithelium differentiation and human sperm and cilia motility. This latter work has characterized the disruption in disease of multiciliogenesis master regulators, essential axoneme structural proteins and a cytosolic chaperone-mediated network of dynein assembly factors that are required to power and regulate axonemal motor activity. It has revealed links between dynein assembly and intraflagellar transport as a cause of human disease. We are currently engaged in an EU-funded clinical programme to document all human variants causing motile ciliopathies and to thereby reveal the genotype-phenotype correlations that can determine how a patient’s underlying genetics affect their clinical disease expression. This work will help to improve disease understanding and guide future clinical management and interventions.

Ciliopathies are incurable disorders affecting all ages of people and from earliest life. There is urgent need to understand the inter-related structure and functions of sperm and different cilia in the body, in order to translate our biological advances into an improved understanding of disease that can be of benefit to the affected patients. By understanding the molecular causes of ciliopathies, our goal is to develop new genetic medicines that can accurately treat ciliopathy patients according to their underlying gene defect. We are currently developing RNA based drugs to efficiently target different classes of mutations causing motile ciliopathy disease.