Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms
Dinu Antony, Anita Becker-Heck, Maimoona A Zariwala, Miriam Schmidts, Alexandros Onoufriadis, Mitra Forouhan, Robert Wilson, Theresa Taylor-Cox, Ann Dewar, Claire Jackson, Patricia Goggin, Niki T Loges, Heike Olbrich, Martine Jaspers, Mark Jorissen, Margaret W Leigh, Whitney E Wolf, M Leigh Anne Daniels, Peadar G Noone, Thomas W Ferkol, Scott D Sagel, Margaret Rosenfeld, Andrew Rutman, Abhijit Dixit, Christopher O'Callaghan, Jane S Lucas, Claire Hogg, Peter J Scambler, Richard D Emes, Uk10k, Eddie M K Chung, Amelia Shoemark, Michael R Knowles, Heymut Omran, Hannah M Mitchison, Saeed Al-Turki, Carl Anderson, Dinu Antony, Inês Barroso, Phil Beales, Jamie Bentham, Stefano Bertolini, Shoumo Bhattacharya, Sebastiano Calandra, Keren Carss, Krishna Chatterjee, Sebhattin Cirak, Catherine Cosgrove, Allan Daly, Petr Danecek, Richard Durbin, David Fitzpatrick, Jamie Floyd, Reghan Foley, Chris Franklin, Marta Futema, Colin Graham, Steve Humphries, Matt Hurles, Chris Joyce, Eran Leitersdorf, Shane McCarthy, Hannah M Mitchison, Dawn Muddyman, Francesco Muntoni, Andrew Neil, Stephen O'Rahilly, Alexandros Onoufriadis, Victoria Parker, Felicity Payne, Vincent Plagnol, Lucy Raymond, David B Savage, Peter Scambler, Miriam Schmidts, Nadia Schoenmakers, Mary Seed, Robert Semple, Eva Serra, Jim Stalker, Frank Van Bockxmeer, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Klaudia Walter, Ros Whittall, Kathy Williamson, Dinu Antony, Anita Becker-Heck, Maimoona A Zariwala, Miriam Schmidts, Alexandros Onoufriadis, Mitra Forouhan, Robert Wilson, Theresa Taylor-Cox, Ann Dewar, Claire Jackson, Patricia Goggin, Niki T Loges, Heike Olbrich, Martine Jaspers, Mark Jorissen, Margaret W Leigh, Whitney E Wolf, M Leigh Anne Daniels, Peadar G Noone, Thomas W Ferkol, Scott D Sagel, Margaret Rosenfeld, Andrew Rutman, Abhijit Dixit, Christopher O'Callaghan, Jane S Lucas, Claire Hogg, Peter J Scambler, Richard D Emes, Uk10k, Eddie M K Chung, Amelia Shoemark, Michael R Knowles, Heymut Omran, Hannah M Mitchison, Saeed Al-Turki, Carl Anderson, Dinu Antony, Inês Barroso, Phil Beales, Jamie Bentham, Stefano Bertolini, Shoumo Bhattacharya, Sebastiano Calandra, Keren Carss, Krishna Chatterjee, Sebhattin Cirak, Catherine Cosgrove, Allan Daly, Petr Danecek, Richard Durbin, David Fitzpatrick, Jamie Floyd, Reghan Foley, Chris Franklin, Marta Futema, Colin Graham, Steve Humphries, Matt Hurles, Chris Joyce, Eran Leitersdorf, Shane McCarthy, Hannah M Mitchison, Dawn Muddyman, Francesco Muntoni, Andrew Neil, Stephen O'Rahilly, Alexandros Onoufriadis, Victoria Parker, Felicity Payne, Vincent Plagnol, Lucy Raymond, David B Savage, Peter Scambler, Miriam Schmidts, Nadia Schoenmakers, Mary Seed, Robert Semple, Eva Serra, Jim Stalker, Frank Van Bockxmeer, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Klaudia Walter, Ros Whittall, Kathy Williamson
Abstract
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed "radial spoke defect." We sequenced CCDC39 and CCDC40 in 54 "radial spoke defect" families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by "null" alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as "IDA and microtubular disorganisation defect," rather than "radial spoke defect."
Conflict of interest statement
The authors have no conflicts of interest to declare.
© 2012 Wiley Periodicals, Inc.
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Source: PubMed