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.

The dynamics of protein localisation to restricted zones within Drosophila mechanosensory cilia

“…In our current understanding, especially from studies in unicellular organisms such as the biflagellate Chlamydomonas reinhardtii, dynein motor complexes are pre-assembled within the cytoplasm before transport into the cilium and docking on the axoneme (Fowkes and Mitchell, 1998). Pre-assembly requires dedicated co-chaperone assembly factors (generally known as DNAAFs) (Desai et al, 2018; Horani and Ferkol, 2013) (Fig. 1B).…”

The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

“…Of interest are PCD mutations that identify genes required not for dynein components, but for dynein complex assembly and transport. Three stages are thought to constitute the biogenesis of dynein arms: cytoplasmic pre-assembly of multiple subunits into dynein complexes (Fok et al, 1994;Fowkes and Mitchell, 1998), transfer of the complexes into the ciliary compartment, and intraflagellar transport (IFT) along the axoneme (Horani and Ferkol, 2013). The pre-assembly of the dynein HCs may be further divided into two phases: the folding and stabilisation of globular head domains of HCs, and the assembly of HCs onto the IC dimer scaffold with incorporation of LCs (Mitchison et al, 2012).…”