Splice-Site Mutations in the Axonemal Outer Dynein Arm Docking Complex Gene CCDC114 Cause Primary Ciliary Dyskinesia

Onoufriadis, Alexandros; Paff, Tamara; Antony, Dinu; Shoemark, Amelia; Micha, Dimitra; Kuyt, Bertus; Schmidts, Miriam; Petridi, Stavroula; Dankert-Roelse, J.E.; Haarman, Eric G.; Daniëls, Hans; Emes, Richard D.; Wilson, Robert; Hogg, Claire; Scambler, Peter J.; Chung, Eddie M.K.; Pals, Gerard; Mitchison, Hannah M.

doi:10.1016/j.ajhg.2012.11.002

Cited by 171 publications

(157 citation statements)

References 52 publications

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“…Presumably, DC3 has an as yet unidentified regulatory function. DC2 is well conserved throughout evolution, and seems to have undergone duplication in humans (CCDC63 and CCDC114) (22,23). Defects in CCDC114 are known to cause PCD and the patients lack outer dynein arms, suggesting that DC2 functions in OAD docking in humans also (22,23).…”

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confidence: 99%

“…DC2 is well conserved throughout evolution, and seems to have undergone duplication in humans (CCDC63 and CCDC114) (22, 23). Defects in CCDC114 are known to cause PCD and the patients lack outer dynein arms, suggesting that DC2 functions in OAD docking in humans also (22,23). The ODA-DC binds OAD via at least three interactions: one between DC1 and the OAD intermediate chain IC1, one between DC1 and the other OAD intermediate chain IC2, and one between DC2 and the OAD light chain LC7b (24, 25).…”

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Cooperative binding of the outer arm-docking complex underlies the regular arrangement of outer arm dynein in the axoneme

Owa

Furuta

Usukura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Outer arm dynein (OAD) in cilia and flagella is bound to the outer doublet microtubules every 24 nm. Periodic binding of OADs at specific sites is important for efficient cilia/flagella beating; however, the molecular mechanism that specifies OAD arrangement remains elusive. Studies using the green alga Chlamydomonas reinhardtii have shown that the OAD-docking complex (ODA-DC), a heterotrimeric complex present at the OAD base, functions as the OAD docking site on the doublet. We find that the ODA-DC has an ellipsoidal shape ∼24 nm in length. In mutant axonemes that lack OAD but retain the ODA-DC, ODA-DC molecules are aligned in an end-to-end manner along the outer doublets. When flagella of a mutant lacking ODA-DCs are supplied with ODA-DCs upon gamete fusion, ODA-DC molecules first bind to the mutant axonemes in the proximal region, and the occupied region gradually extends toward the tip, followed by binding of OADs. This and other results indicate that a cooperative association of the ODA-DC underlies its function as the OAD-docking site and is the determinant of the 24-nm periodicity.C ilia and flagella of eukaryotic cells are organelles that generate fluid flow on the cell surface and/or sense chemical or mechanical stimuli from the external environment (1). Cilia/flagella beating is driven by outer arm dynein (OAD) and inner arm dyneins. The arrangement of dyneins on the axoneme has an overall periodicity of 96 nm, within which OAD binds every 24 nm; this 24-nm periodicity is completely conserved in essentially all eukaryotic organisms with "9 + 2" axonemes (2, 3) and even occurs in insect sperm flagella containing multiple rows of doublet microtubules arranged in a spiral configuration (4, 5). OAD is best characterized in Chlamydomonas. It is a very large protein complex of ∼2 MDa, comprising 3 heavy chains, 2 intermediate chains, and 11 distinct light chains. Most of the subunits are conserved from protists to mammals (6). OAD is the most abundant and most powerful axonemal dynein, generating about twothirds of the total propulsive force of ciliary beating (7,8). Human diseases due to ciliary motility defects [termed primary ciliary dyskinesia (PCD)] are caused most commonly by defects in OAD assembly (9-11). The assembly process and the in situ structure of the OAD complex in the axoneme have been well studied (3, 12, 13). However, the mechanism underlying the periodic binding of OAD to the doublet is poorly understood.The outer dynein arm-docking complex (ODA-DC) has been identified as a complex that mediates OAD binding to the doublet (14, 15). In the flagella of Chlamydomonas mutants (e.g., outerdynein-arm deficient oda6) retaining the ODA-DC but not OAD, the ODA-DC is observed by electron microscopy as a small projection linearly arrayed every 24 nm along the outer doublet (3,(14)(15)(16)(17). It is composed of three subunits: DC1, ∼83 kDa, encoded by ODA3; DC2, ∼62 kDa, encoded by ODA1; and DC3, ∼21 kDa, encoded by ODA14 (18-20), which assemble in the cell cytoplasm and are transported into the fla...

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confidence: 99%

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confidence: 99%

Cooperative binding of the outer arm-docking complex underlies the regular arrangement of outer arm dynein in the axoneme

Owa

Furuta

Usukura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, mutations in RSPH1 (a mutation in a gene coding for one of the radial spoke subunits) reportedly cause a mild phenotype [69]. Male patients with mutations in CCDC114 (coding for a docking protein for the ODA) are generally fertile [70]. Situs abnormalities are not observed in patients with mutations affecting the central pair [64] or radial spokes [49,50,69], nor in patients with reduced generation of multiple motile cilia [13,14].…”

Section: Genetics: Pcd Is Generally An Autosomal Recessive Disease Tmentioning

confidence: 99%

“…In addition, mutations in 3 genes have been described that, though not coding for proteins that are structurally part of the ODA, cause selective absence of ODA on TEM: CCDC114 [70], CCDC151[80] and ARMC4 [81]. These genes code for ODA-associated docking complex proteins that enable attachment of the ODA to the axoneme.…”

Section: Genetics: Pcd Is Generally An Autosomal Recessive Disease Tmentioning

confidence: 99%

Diagnostic Methods in Primary Ciliary Dyskinesia

Lucas

Paff

Goggin

et al. 2016

Paediatric Respiratory Reviews

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Educational Aims; The reader will be able to; Describe the basis of the various diagnostic tests for PCD  Have an understanding of the strengths and limitations of each test  Understand that there is no 'gold standard' test  Understand why highly specialised centres should analyse samples and interpret results. Page 2 of 36A c c e p t e d M a n u s c r i p t  SummaryDiagnosing primary ciliary dyskinesia is difficult. With no reference standard, a combination of tests is needed; most tests require expensive equipment and specialist scientists. We review the advances in diagnostic testing over the past hundred years, with emphasis on recent advances.We particularly focus on use of high-speed video analysis, transmission electron microscopy, nasal nitric oxide and genetic testing. We discuss the international efforts that are in place to advance the evidence base for diagnostic tests.

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“…Recent studies in Chlamydomonas suggest that ODA10 (CCDC151 in humans), ODA5 (homolog of a DC2-like protein CCDC63), and ODA8 (LRRC56 in humans) form an accessory complex of the ODA-DC [153,155,156]. The complex is associated with an adenylate kinase with sequence similarity to human cytosolic AK1 and AK5 [155].…”

Section: Factors For Intraciliary Docking and Regulation Of Oadmentioning

confidence: 99%