Molecular Genetics of Primary Ciliary Dyskinesia

Abstract Primary ciliary dyskinesia (PCD) is a genetic disease of the motile cilia, and is part of a rapidly expanding collection of disorders collectively known as ciliopathies. Our understanding of the complex genetics and functional phenotypes of these conditions has rapidly advanced over the past decade. A growing number of cilia‐related genes and mutations have been identified, which segregate into genes that encode axonemal motor proteins, structural and regulatory proteins within the cilium, as well as an emerging class of cytoplasmic proteins involved in ciliary assembly. These findings have yielded unexpected insights into the processes involved in the assembly, structure and function of a cilium, which will allow us to better understand the clinical heterogeneity of disease. Moreover, these discoveries have the potential to revolutionise testing for PCD, and lead to earlier diagnosis and treatment of affected individuals. Key Concepts: Cilia are complex organelles that are on the surface of many cell types and involved in diverse cellular functions. Cilia are broadly classified as motile (motor) or primary (sensory), and the latter are important signalling organelles that sense the extracellular environment. Motile cilia are critical for the intrinsic defence of the respiratory tract, including the middle ear, paranasal sinuses, and conducting airways. Primary ciliary dyskinesia is an inherited disease that is characterised by impaired ciliary function and leads to diverse clinical manifestations, including chronic sinopulmonary disease, persistent middle ear effusions, laterality defects and infertility. Mutations in different primary ciliary dyskinesia‐associated genes that encode proteins involved in ciliary assembly, structure and function can produce similar clinical phenotypes but different ultrastructural defects.