PCD Genes—From Patients to Model Organisms and Back to Humans

Abstract

Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000–20,000 individuals and is caused by mutations in at least 50 genes. The past twenty years brought significant progress in the identification of PCD-causative genes and in our understanding of the connections between causative mutations and ciliary defects observed in affected individuals. These scientific advances have been achieved, among others, due to the extensive motile cilia-related research conducted using several model organisms, ranging from protists to mammals. These are unicellular organisms such as the green alga Chlamydomonas, the parasitic protist Trypanosoma, and free-living ciliates, Tetrahymena and Paramecium, the invertebrate Schmidtea, and vertebrates such as zebrafish, Xenopus, and mouse. Establishing such evolutionarily distant experimental models with different levels of cell or body complexity was possible because both basic motile cilia ultrastructure and protein composition are highly conserved throughout evolution. Here, we characterize model organisms commonly used to study PCD-related genes, highlight their pros and cons, and summarize experimental data collected using these models.

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

“…Mutations in more than 50 different genes cause PCD by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT) (11,12). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotypephenotype relationships, and studying the cell biology of cilia (1,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Despite these findings, we still lack effective treatments, and people with PCD have significant upper and lower airway impairment (6,19,24).…”

Mutations in CFAP47, a previously reported MMAF causative gene, also contribute to the respiratory defects in patients with PCD

“…The specific phenotypes or severity of PCD symptoms depend upon the extent of the alterations of cilia/ flagella structure and function, which is directly or indirectly caused by the mutated genes. To date, approximately 50 genes have been reported to be involved in PCD, although they are estimated to account for only 60%-70% of PCD cases (Niziolek et al, 2022). There are still many individuals with PCD for whom no known causative genes were identified, indicating the involvement of other potential novel pathogenic genes.…”

“…Primary ciliary dyskinesia (PCD, MIM 244400) is a rare genetic disease, characterized by abnormal ultrastructures and/or dysfunction of motile cilia. PCD affects approximately 1/10,000–1/20,000 individuals, but the actual prevalence is probably underestimated (Niziolek et al, 2022). PCD patients in the neonatal period have a wet cough caused by recurrent infections of the upper and lower respiratory tract and frequently exhibit sinusitis, otitis media, and hearing defects.…”

Reduced dosage of multiple dynein arm preassembly factors limits cilia regeneration inChlamydomonas reinhardtii

“…Motile cilia are microtubule-based organelles that generate fluid flow or provide cellular motility [1]. In humans, pathogenic variants in more than 58 genes cause a rare disease called primary ciliary dyskinesia (PCD), characterized by recurrent lung infections, neonatal respiratory distress, bronchiectasis, otitis media, situs inversus/ambiguus, and male infertility [2][3][4][5][6]. Chlamydomonas reinhardtii, a haploid, single-celled, photosynthetic alga, has been used extensively for the study of motile cilia due to its ease of genetic, biochemical, and microscopic analyses.…”