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The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation


Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.

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Figure 1: Mutation of Ccdc40 in lnks mice results in laterality defects.
Figure 2: Mutation of zebrafish ccdc40 in lok mutants or knockdown of ccdc40 in morpholino-injected embryos produces laterality defects.
Figure 3: Loss of Ccdc40 results in ciliary defects.
Figure 4: Localization of DNAH5, GAS11 and DNALI1 in respiratory epithelial cells from individuals with PCD carrying CCDC40 mutations.
Figure 5: CCDC40 mutations affect localization of CCDC39 in respiratory cells.

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We thank the German subject support group 'Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.', S. Glaser for the initial genomic mapping of lok, J. Liu for help with imaging Ccdc40 protein expression in the mouse node, L. Bulwith, A. Heer, C. Kopp, D. Nergenau and K. Sutter for excellent technical assistance, and D. Bosco for zebrafish facility maintenance. We also thank M. Griese (Munich), E.v. Mutius (Munich), T. Nuesslein (Koblenz), N. Schwerk (Hannover), S. Reithmayr (Vienna), H. Seithe (Nuernberg) and M. Stern (Tuebingen) for supporting the study. The lnks mutant mouse line was established as part of the Sloan-Kettering Institute Mouse Project (R37-HD035455). This work was supported by the Basil O'Connor Award from the March of Dimes, the Young Investigator Award from the Spina Bifida Association and R01-HD058629 to I.E.Z.; the German Human Genome Project DHGP grant 01 KW9919 to R.G.; the Howard Hughes Medical Institute to L.N.; 'Deutsche Forschungsgemeinschaft' DFG Om 6/4, GRK1104 and the SFB592 to H.O.; and NICHD-R01HD048584 to R.D.B.

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Studies in mice were conducted by I.E.Z., A.P., A.B.-H., H. Omran, K.V.A. and L.N. Studies in zebrafish were conducted by N.O., K.B.L., J.S.-B., J.M., R.G. and R.D.B. Studies with human samples were conducted by A.B.-H., N.T.L., H. Olbrich, K.H., M.F., J.H., R.R., K.G.N., J.K.M., G.B. and H. Omran. The manuscript was prepared by A.B.-H., I.E.Z., L.N., H. Omran and R.D.B.

Corresponding authors

Correspondence to Lee Niswander, Heymut Omran or Rebecca D Burdine.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1 (PDF 9961 kb)

Supplementary Video 1

Cilia motility in control cells from a nasal brush biopsy (AVI 3432 kb)

Supplementary Video 2

Defective cilia motility in patient OP76II1 (AVI 2086 kb)

Supplementary Video 3

Defective cilia motility in patient OP82II1 (AVI 5697 kb)

Supplementary Video 4

Defective cilia motility in patient OP87II2 (AVI 3471 kb)

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Becker-Heck, A., Zohn, I., Okabe, N. et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet 43, 79–84 (2011).

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