Table 1. Currently known causal primary ciliary dyskinesia (PCD) genes.
| Ultrastructural defect category | Gene | TEM defect/Function | % of PCD cases | References | Model organism | SD | NRD | RI | B | OM | Fertility affected | Ciliary beat characteristic |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Outer dynein arm defect | DNAH5 | ODA defects/Dynein arm component | ~15-20% | [68–70] | NA | Yes | Yes | Yes | Yes | Yes | NA | Immotile cilia |
| DNAI1 | ODA defects/ODA component | ~10% | [59,71,72] | Chlamydomonas | Yes | Yes | Yes | Yes | Yes | Yes | Immotile cilia | |
| NME8/ TXNDC3 | ODA defects/ODA component | Rare | [61] | Sea urchin | Yes | NA | Yes | Yes | Yes | NA | Normal beat frequency | |
| DNAI2 | ODA defects/ODA component | ~2% | [73,104] | Chlamydomonas | Yes | NA | Yes | Yes | Yes | Yes | Immotile cilia | |
| DNAL1 | ODA defects/ODA component | Rare | [74] | Chlamydomonas | Yes | NA | Yes | Yes | Yes | NA | Weak or no movement | |
| ARMC4 | ODA defects/Docking and targeting of ODA components | ~6% | [76,77] | Mouse, Zebrafish | Yes | Yes | Yes | Yes | Yes | NA | Reduced frequency or amplitude and immotility | |
| CCDC114 | ODA defects/Docking of ODAs to microtubules | ~4% | [78,79] | Chlamydomonas | Yes | Yes | Yes | Yes | Yes | No | Reduced frequency, dyskinetic or immotile | |
| CCDC151 | ODA defects; ODA and IDA defects1/Assembly of ODAs and ODA docking complexes | NA | [80], [105] | Zebrafish, Mouse, Planaria | Yes | Yes | Yes | Yes | Yes | NA | Immotile cilia | |
| Outer and inner dynein arm defects | CCDC103 | ODA and IDA defects/Anchoring of dynein arms to microtubules | Rare | [65] | Zebrafish, Chlamydomonas | Yes | Yes | Yes | Yes | Yes | NA | Reduced amplitude, uncoordinated or immotile |
| DNAAF3 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | Rare | [60] | Chlamydomonas | Yes | Yes | Yes | Yes | Yes | NA | Immotile cilia | |
| DNAAF1/ LRRC50 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | 2-5% | [81,83] | Zebrafish, Chlamydomonas | Yes | NA | Yes | Yes | Yes | Yes* | Immotile cilia | |
| DNAAF2/ Ktu | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | ~2% | [63] | Medaka, Chlamydomonas | Yes | NA | Yes | Yes | Yes | Yes | Immotile cilia | |
| LRRC6 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs, transcriptional regulation of dynein arm components | ~3% | [84,106,107] | Zebrafish, Drosophila, Chlamydomonas | Yes | Yes | Yes | Yes | Yes | Yes* | Immotile cilia | |
| HEATR2 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | Rare | [85] | Chlamydomonas | Yes | Yes | Yes | NA | Yes | Yes | Reduced motility | |
| ZMYND10 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs, transcriptional regulation of dynein arm components | ~5% | [86,87] | Zebrafish, Xenopus | Yes | Yes | Yes | Yes | Yes | Yes* | Immotile cilia | |
| C21orf59 | Loss of ODAs and IDAs/Possible adaptor protein for ODA and IDA transport | ~1% | [88] | Chlamydomonas Zebrafish, Planaria | Yes | Yes | Yes | Yes | Yes | NA | Immotile cilia | |
| SPAG1 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | ~3% | [89] | Zebrafish | Yes | Yes | Yes | Yes | Yes | NA | Stiff and immotile cilia | |
| DYX1C1 | ODA and IDA defects/Cytoplasmic assembly of IDAs and ODAs | ~3% | [66] | Mouse, Zebrafish | Yes | Yes | Yes | Yes | Yes | Yes | Immotile cilia | |
| Inner Dynein Arm/Dynein regulatory complex defects | CCDC40 | Central microtubule pair, IDA and Nexin-DRC defects/Assembly of Nexin-DRC complexes and role in IDA attachment | 2-7% | [90,91] | Mouse, Zebrafish | Yes | Yes | Yes | Yes | Yes | Yes | Reduced amplitude or immotile cilia |
| CCDC39 | Central microtubule pair, IDA and Nexin-DRC defects/Assembly of Nexin-DRCs and role in IDA attachment | 2-6% | [67,91,92] | Dog, Zebrafish | Yes | Yes | Yes | Yes | Yes | Yes | Reduced amplitude and defective beat regulation | |
| CCDC65 | Defects in IDAs and nexin links and microtubule disorganization2/ Dynein regulatory complex component | Rare | [88,103] | Chlamydomonas, Zebrafish, Planaria | No | Yes | Yes | Yes | Yes | NA | Stiff, dyskinetic cilia | |
| DRC1/ CCDC164 | Missing nexin links/Dynein regulatory complex component | Rare | [64] | Chlamydomonas | No | Yes | Yes | Yes | Yes | NA | Increased beat frequency with reduced amplitude of bending | |
| Central pair defects | RSPH4A | Central microtubule pair defects3/Radial spoke protein | ~2% | [57,95] | Zebrafish, Chlamydomonas, Mouse | No | Yes | Yes | Yes | Yes | Yes | Rotational, uncoordinated movement |
| RSPH9 | Central microtubule pair defects3/Radial spoke protein | ~1% | [57,95] | Zebrafish, Chlamydomonas, Mouse | No | NA | Yes | Yes | Yes | Yes | Rotational movement | |
| HYDIN | Central microtubule pair composition3 | Rare | [96] | Zebrafish, Drosophila | No | Yes | Yes | Yes | Yes | NA | Uncoordinated and reduced beat amplitude | |
| RSPH1 | Central microtubule pair and radial spoke defects/Radial spoke protein | ~2-3% | [57,58] | NA | No | Yes | Yes | Yes | Yes | Yes* | Reduced frequency | |
| No ultrastructural defects | DNAH11 | No ultrastructural defects/Dynein heavy chain subunit | ~6-7% | [62,97] | Chlamydomonas, Mouse | Yes | NA | Yes | Yes | Yes | No | Stiff, hyperkinetic beat |
| Other | OFD14 | NA; Centrosomal and primary cilia basal body protein; possibly involved in intraflagellar transport | NA | [42,108,109] | Mouse | NA | Yes | Yes | NA | NA | NA | Uncoordinated and disorganized beat |
| RPGR5 | Missing dynein arms, central pair and/or nexin links | NA | [43–45,110–117] | Dog, Zebrafish, Mouse | No | No | Yes | Yes | Yes | No | Mix of motile and immotile cilia | |
| CCNO6 | NA; Mother centriole amplification and maturation during apical docking | NA | [46] | Xenopus | No | Yes | Yes | Yes | NA | Yes* | No obvious beating defects | |
| MCIDAS6 | NA; Required for deuterosome-mediated acentriolar pathway; transcriptional activator of genes required for centriole formation | NA | [47,118–120] | Xenopus | No | Yes | Yes | Yes | Yes | Yes* | Immotile cilia | |
| DNAH87 | NA | NA | [121] | NA | NA | NA | NA | NA | NA | NA | NA |
*
Infertility or subfertility observed in female PCD patients as well.
1
Different transmission electron microscopy (TEM) defects were observed in different populations of PCD patients with mutations in CCDC151.
2
Microtubule disorganization was found in 5-15% of patients; Horani et al. [103] did not observe any ultrastructural defects in their cohort of patients with CCDC65 mutations, suggesting that mutations in CCDC65 cause mild structural defects.
3
Defects were seen in a small proportion of cilia; most ciliary ultrastructure appeared normal.
4
PCD is associated with X-linked mental retardation.
5
PCD is associated with X-linked retinitis pigmentosa.
6
CCNO and MCIDAS cause a PCD-like phenotype classified as reduced generation of multiple motile cilia (RGMC).
7
This is a preliminary finding of two null mutations in DNAH8 in one patient. Functional studies of the mutation and also investigation of the ultrastructural and ciliary beat phenotypes have not been reported.
B, bronchiectasis; DRC, dynein regulatory complex; IDA, inner dynein arm; ODA, outer dynein arm; OM, otitis media; NA, not available; NRD, neonatal respiratory distress; RI, respiratory infection; SD, situs defect;