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

Anita Becker-Heck, Irene E. Zohn, Noriko Okabe, Andrew Pollock, Kari Baker Lenhart, Jessica Sullivan-Brown, Jason McSheene, Niki T. Loges, Heike Olbrich, Karsten Haeffner, Manfred Fliegauf, Judith Horvath, Richard Reinhardt, Kim G. Nielsen, June K. Marthin, Gyorgy Baktai, Kathryn V. Anderson, Robert Geisler, Lee Niswander, Heymut OmranRebecca D. Burdine

Research output: Contribution to journalArticle

171 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)79-84
Number of pages6
JournalNature Genetics
Volume43
Issue number1
DOIs
StatePublished - Jan 2011

All Science Journal Classification (ASJC) codes

  • Genetics

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    Becker-Heck, A., Zohn, I. E., Okabe, N., Pollock, A., Lenhart, K. B., Sullivan-Brown, J., McSheene, J., Loges, N. T., Olbrich, H., Haeffner, K., Fliegauf, M., Horvath, J., Reinhardt, R., Nielsen, K. G., Marthin, J. K., Baktai, G., Anderson, K. V., Geisler, R., Niswander, L., ... Burdine, R. D. (2011). The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nature Genetics, 43(1), 79-84. https://doi.org/10.1038/ng.727