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Bench To Bedside: New Findings in Primary Ciliary Dyskinesia

By Joseph H. Sisson, MD; and Johnny L. Carson, PhD

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The Search for PCD Candidate Genes

Among the organelles of the eukaryotic cell, cilia and flagella arguably provide the most striking example of the relatedness of structure and function; by extension, the failure of ciliary motility associated with the syndrome PCD provides a contrasting view of functional failure associated with structural disorganization. Inasmuch as the major proteomic constituents of ciliary and flagellar axonemes are highly conserved across the phylogenetic spectrum, it was hypothesized early on that examination of motility mutants of eukaryotic protists could provide new insights into candidate genes related to PCD.²⁶ Indeed, several studies using the candidate gene approach have provided promising insights into the molecular genetics of PCD.

The efforts to identify PCD candidate genes have also provided insights that may exclude certain candidates. A human axonemal dynein heavy chain gene, DNAH9, with considerable homology to a sea urchin axonemal heavy chain dynein, has been characterized.³⁹ However, in a genotype analysis performed in 31 PCD families, only two families were identified as having concordant inheritance of DNAH9 alleles in affected individuals. A mutation search revealed only polymorphic variants, suggesting that DNAH9 does not represent a PCD candidate gene. This experience points out the difficulty in associating genetic variations with genetic cause and effect.

The appearance of abnormal organ situs in a subset of patients with PCD also has prompted the search for a molecular-level explanation for this phenomenon. The transcription factor FOXJ1 (previously HFH-4 or FKHL13) is temporally related to ciliogenesis,³⁹ as well as to correct positioning of the viscera.⁴⁰ However, mutations of FOXJ1 have not been identified among patients with PCD,⁴¹ suggesting that axonemal assembly during ciliogenesis is a multigeneic event. In a similar vein, mutations of DNAH5 have been shown to be associated with randomization of left-right asymmetry.³² In terms of candidate genes, this is a noteworthy observation inasmuch as this gene encodes a protein highly similar to the Chlamydomonas g-dynein heavy chain.

Table 1—Candidate Gene Studies
Candidate/Human	Protein Affected	Defect	References
Chlamydomonas reinhardtii IC78 Human DNAI1	Dynein intermediate chain	Outer arm	27-29
Chlamydomonas reinhardtii IC69 Human DNAI2	Dynein intermediate chain	Outer arm	30
Mouse Mdnah5 Human DNAH5	Dynein heavy chain	Outer arm	31-33
Drosophila Dhc36C Human DNAH7	Dynein heavy chain	Inner arm	34
Mouse DNAH11 Human DNAH11	Dynein heavy chain		35,36
Chlamydomonas reinhardtii pf20 Human hPF20	Not applicable	Central complex	37
Chlamydomonas reinhardtii Human hRSHL1	Radial spokehead-like protein	Radial spokehead	38

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