Recent advances in primary ciliary dyskinesia genetics

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetically heterogeneous disorder caused by the abnormal structure and/or function of motile cilia. The PCD diagnosis is challenging and requires a well-described clinical phenotype combined with the identification of abnormalities in ciliary ultrastructure and/or beating pattern as well as the recognition of genetic cause of the disease. Regarding the pace of identification of PCD-related genes, a rapid acceleration during the last 2-3 years is notable. This is the result of new technologies, such as whole-exome sequencing, that have been recently applied in genetic research. To date, PCD-causative mutations in 29 genes are known and the number of causative genes is bound to rise. Even though the genetic causes of approximately one-third of PCD cases still remain to be found, the current knowledge can already be used to create new, accurate genetic tests for PCD that can accelerate the correct diagnosis and reduce the proportion of unexplained cases. This review aims to present the latest data on the relations between ciliary structure aberrations and their genetic basis.

Keywords: Cell biology; Diagnostics; Genetics; Molecular genetics.

Figure 1

Schematic diagram of the ciliary axoneme in Chlamydomonas. Upper left: longitudinal section of a cilium presenting the location of axonemal microtubules in different parts of the cilium. Red line indicates the site of a cross section presented on the right site. The cross section shows nine microtubule doublets surrounding the central pair of microtubules. The microtubules are interconnected via radial spokes, N-DRCs and dynein arms; no dynein arms are present in the transition region. All these structures except ODA are distributed with the 96 nm periodicity along the axoneme; ODA are present every 24 nm. The placement of all these structures in relation to each other within the 96 nm repeat is depicted at the bottom. a/d, b/g, c and e, single-headed IDA isoforms; fα and fβ, double-headed IDA isoform f; IC/LC, intermediate chain-light chain complex of inner dynein arms (IDA); Mt A, microtubule A; Mt B, microtubule B; N-DRC, nexin-dynein regulatory complex; ODA, outer dynein arms with marked α, β and γ heavy chains; RS1, radial spoke 1, RS2; radial spoke 2; RS3S, radial spoke 3 stump. Scheme based on the original data published previously.

Figure 2

The probable localisation of identified primary ciliary dyskinesia (PCD) genes products within the human ciliary structure components. The schemes of human axonemal complexes are adapted from Chlamydomonas data. The proteins related to PCD are indicated in purple and their names are provided. Cytoplasmic proteins involved in PCD phenotype are listed in the box on the right. (A) ODA consists of heavy dynein chains β and γ (comprising a tail, the AAA-ring-like structure, which is a motor unit, and the stalk with MTBD and coiled-coil protrusion called strut or buttress, which strengthens the base of the stalk), LCs, ICs and DC proteins. (B) N-DRC consists of the base plate and linker that further comprises proximal and distal lobes. (C) CP scheme involves microtubules C1 and C2 with their projections (including C2b) interconnected by a bipartite bridge and diagonal linker. (D) RS structure is depicted in a cross-sectional (left) and a bottom (right) view. RSPH1, 4A and 9 are components of RS head (pink). CP, central pair; DC, docking complex; IC, intermediate chain; IDA, inner dynein arm; LC, light chain; Mt A and B, microtubule A and B; MTBD, microtubule binding domain; N-DRC, nexin-dynein regulatory complex; ODA, outer dynein arm; RS, radial spoke; β and γ, dynein heavy chains β and γ. Schemes based on the original data published previously.