Mini-symposium: Primary Ciliary Dyskinesia
Genetics and biology of primary ciliary dyskinesia

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Summary

Ciliopathies are a growing class of disorders caused by abnormal ciliary axonemal structure and function. Our understanding of the complex genetic and functional phenotypes of these conditions has rapidly progressed. Primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. However, unlike many Mendelian genetic disorders, PCD is not caused by mutations in a single gene or locus, but rather, autosomal recessive mutation in one of many genes that lead to a similar phenotype. The first reported PCD mutations, more than a decade ago, identified genes encoding known structural components of the ciliary axoneme. In recent years, mutations in genes encoding novel cytoplasmic and regulatory proteins have been discovered. These findings have provided new insights into the functions of the motile cilia, and a better understanding of motile cilia disease. Advances in genetic tools will soon allow more precise genetic testing, mandating that clinicians must understand the genetic basis of PCD. Here, we review genetic mutations, their biological impact on cilia structure and function, and the implication of emerging genetic diagnostic tools.

Section snippets

Cilia types and ciliopathies

Cilia are segregated into two classes, motile and primary. Syndromes associated with defects in cilia of either class are termed ciliopathies. Primary cilia have sensory and signaling roles, and are present on most non-dividing cells, with prominent functions in osteoblasts, neurons and renal tubule cells during development and for homeostasis [7], [8]. Primary cilia have evolved unique functions in the cells of the retina and inner ear, as well as in the epithelia of the renal tubule, where

Programs of ciliogenesis

Identifying the specific function of proteins that are mutated in PCD is a major challenge, owing to the complexity of the defined and predicted pathways for generation of ciliated cells and the assembly of motile cilia. A mutation in any one of the proteins required to build or regulate the cilium could cause PCD. The assembly of cilia is regulated by several transcription factors, each with their own transcriptome. The identification of regulatory programs has been complemented by the

Animal models for discovery of candidate PCD genes and validation

As noted, a challenge in the field is the identification of candidate genes that may be mutant in PCD, and to determine if a mutation is related to cilia function. The ciliary axoneme is phylogenetically conserved, which has been exploited in PCD gene discovery. Chlamydomonas reinhardtii, a single cell, biflagellated alga that is motile has been widely used [25], [26]. The ability to isolate large quantities of biochemically pure algal flagella has permitted proteomic analysis. These analyses

PCD genetics

PCD is usually inherited as an autosomal recessive trait. However, rare cases of autosomal dominant and X-linked transmission, causing PCD-like phenotype, have been reported [35], [36]. Consanguinity commonly contributes to autosomal recessive inheritance. PCD is often found in closed communities, among geographically or culturally isolated groups and thus, the same mutation may be observed in extended families. Therefore, it is essential that the clinician obtain a careful family history, not

Genes associated with primary ciliary dyskinesia

The mutant genes associated with PCD encode proteins that are involved either in axonemal structural and functional components, regulatory complexes, and ciliary assembly or preassembly complexes. A significant gap in research prevents accurate classification of many ciliary (and PCD-related) proteins into one of these classes. In other cases, such as DNAH5, a protein that we recognize as a portion of the ultrastructure of the outer dynein arm, is in fact, a functional, force-generating protein

Genes associated with reduced cilia numbers

Multiciliated respiratory epithelia average 200 cilia per cell. Reports of subjects with poorly ciliated airway cells have attributed these findings to infection, errors in preparation of pathologic samples, or otherwise to a poorly understood rare disease, termed ciliary aplasia [69], [70], [71]. Some of these subjects presented with clinical symptoms similar to classical PCD, including repeated sinopulmonary infections and infertility. Some rare instances of associated congenital

Mutation tolerance and compound heterozygosity

High throughput sequencing has provided us with novel gene mutations and many variants, raising new questions related to the meaning of sequence variants and null mutations in one or two different alleles that are linked to cilia function. Like many inheritable diseases, the genetic load increases with consanguinity, explaining the higher frequency of identified cases in closed populations [78]. However, it is curious that mutations leading to PCD persist in these families despite their

Genotype-phenotype relationships

While genetic defects have been linked with specific ultrastructural abnormalies of the ciliary axoneme, there has not been clear relationship between ultrastructure, genotypes, and respiratory phenotypes. Historically, clinical and genetic heterogeneity of PCD has complicated efforts to provide a clear genotype-phenotype relationship. Moreover, the onset and progression of respiratory disease has not been systematically evaluated or linked to mutated genes. Multi-national study groups composed

Diagnostic challenges and the role of genetic testing

Routine genetic testing must be put in context of other methods, as the diagnosis of PCD can be challenging using current tools. Historically, transmission electron microscopy has been the gold standard, and identification of consistent defects in axonemal ultrastructure with typical phenotypic features was considered sufficient to make the diagnosis. As discussed above, ultrastructural examination of cilia as a diagnostic test for PCD has significant limitations and drawbacks. As alternatives,

Conclusions

PCD is a heterogenic disease, with mutations found in a relatively large number of genes that code for proteins involved in different points of cilia assembly, structure, and function. The number of genes associated with PCD has rapidly grown, and genetic testing as a diagnostic tool is becoming a reality. Biallelic, disease-causing mutations are currently linked to approximately 70% of known cases, though commercial laboratories test are available for only some of these mutations.

Educational Aims

The reader will come to:

  • 1)

    Appreciate the heterogeneity and complexity of primary ciliary dyskinesia genetics.

  • 2)

    Understand how mutations in affected genes impact cilia structure and regulation, leading to primary ciliary dyskinesia.

  • 3)

    Recognize issues related to the use of genetic testing as a diagnostic tool for primary ciliary dyskinesia.

Future Directions

  • Design and use of DNA microchips for the rapid diagnosis of PCD.

  • Genotype-phenotype mapping to understand the heterogeneity of PCD.

  • Elucidation of the mechanism of cilia assembly and function to allow for gene specific therapies.

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      Citation Excerpt :

      Altogether, our findings validated the correlation between the angular speed of the AOAO and cilia motility on its exterior surface. Primary ciliary dyskinesia (PCD) is a collection of genetic disorders involving abnormal motile cilia ultrastructure and function (Antony et al., 2013; Blanchon et al., 2012; Brennan et al., 2021; Dutcher and Brody, 2020; Horani et al., 2016). Mutations in the CCDC39 gene cause inner dynein arm defects and axonemal disorganization in cilia and have been associated with PCD (Blanchon et al., 2012; Ma et al., 2019; Oda et al., 2014).

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