Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a recessive heterogeneous disorder of motile cilia, affecting one per 15,000-30,000 individuals; however, the frequency of this disorder is likely underestimated. Even though more than 40 genes are currently associated with PCD, in the case of approximately 30% of patients, the genetic cause of the manifested PCD symptoms remains unknown. Because motile cilia are highly evolutionarily conserved organelles at both the proteomic and ultrastructural levels, analyses in the unicellular and multicellular model organisms can help not only to identify new proteins essential for cilia motility (and thus identify new putative PCD-causative genes), but also to elucidate the function of the proteins encoded by known PCD-causative genes. Consequently, studies involving model organisms can help us to understand the molecular mechanism(s) behind the phenotypic changes observed in the motile cilia of PCD affected patients. Here, we summarize the current state of the art in the genetics and biology of PCD and emphasize the impact of the studies conducted using model organisms on existing knowledge.

Keywords: Chlamydomonas; Xenopus; ciliopathies; motile cilia; mouse; zebrafish.

Figure 1

Motile cilium ultrastructure. (a) A schematic representation of the multiciliated cell with marked nucleus (light blue), basal bodies, and cilia. (b) A schematic representation of the cilium cross-section, showing large ciliary complexes (the level of the cross-section marked on (a).

Figure 2

Ultrastructural defects caused by mutations in primary ciliary dyskinesia (PCD)-causative genes. The diagrams show a cross-section of the normal motile cilium with main large complexes and fragments of the axonemes with specific ultrastructural defects observed in PCD (as described on the figure and in the main text). Large complexes: ODA (outer dynein arm, violet), IDA (inner dynein arm, dark blue), RS (radial spoke, orange), N-DRC (nexin–dynein regulatory complex, red), CA (central apparatus, green; the shadow of CA in the diagrams representing structural changes in cilia with mutations in radial spoke proteins illustrates that CA can be missing). Names of the causative genes are in red. * Differences in the ultrastructural changes: DNAH11: minor structural defects detected using cryo-ET; MNS1: reduces number of the assembled ODAs; STK36: abnormalities in CA are rare (~5%); DNAJB13: minor structural defects in the radial spoke neck detected using cryo-ET.